Fab I inhibitors

ABSTRACT

Compounds are disclosed which are Fab I inhibitors and are useful in the treatment bacterial infections.

RELATED APPLICATIONS

This application is a 35 U.S.C. 371 of PCT/US02/10332 filed Apr. 3,2002, which claims priority to U.S. Ser. No. 60/282,225 filed Apr. 6,2001, both of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to pharmaceutically active compounds whichinhibit Fab I and are useful for the treatment of bacterial infections.

BACKGROUND OF THE INVENTION

While the overall pathway of saturated fatty acid biosynthesis issimilar in all organisms, the fatty acid synthase (FAS) systems varyconsiderably with respect to their structural organization. Vertebratesand yeast possess a FAS in which all the enzymatic activities areencoded on one or two polypeptide chains, respectively, and the acylcarrier protein (ACP) is an integral part of the complex. In contrast,in bacterial FAS, each of the reactions is catalyzed by a distinct,mono-functional enzyme and the ACP is a discrete protein. Therefore,there is considerable potential for the selective inhibition of thebacterial system by antibacterial agents.

Fab I (previously designated EnvM) functions as an enoyl-ACP reductase(Bergler, et al, (1994), J. Biol. Chem. 269, 5493–5496) in the finalstep of the four reactions involved in each cycle of bacterial fattyacid biosynthesis. In this pathway, the first step is catalyzed byβ-ketoacyl-ACP synthase, which condenses malonyl-ACP with acetyl-CoA(FabH, synthase III). In subsequent rounds, malonyl-ACP is condensedwith the growing-chain acyl-ACP (FabB and FabF, synthases I and II,respectively). The second step in the elongation cycle is ketoesterreduction by NADPH-dependent β-ketoacyl-ACP reductase (FabG). Subsequentdehydration by β-hydroxyacyl-ACP dehydrase (either FabA or FabZ) leadsto trans-2-enoyl-ACP, which in turn is converted to acyl-ACP byNADH-dependent enoyl-ACP reductase (Fab I). Further rounds of thiscycle, adding two carbon atoms per cycle, eventually lead topalmitoyl-ACP (16C), where upon the cycle is stopped largely due tofeedback inhibition of Fab I by palmitoyl-ACP (Heath, et al, (1996), J.Biol. Chem. 271, 1833–1836). Thus, Fab I is a major biosynthetic enzymeand is a key regulatory point in the overall synthetic pathway ofbacterial fatty acid biosynthesis. Therefore, Fab I is an ideal targetfor antibacterial intervention.

Studies have shown that diazaborine antibiotics inhibit fatty acid,phospholipid and lipopolysaccharide (LPS) biosynthesis and that theantibacterial target of these compounds is Fab I. For example,derivative 2b18 from Grassberger, et al, (1984) J. Med Chem 27, 947–953has been reported to be a non-competitive inhibitor of Fab I (Bergler,et al, (1994) J. Biol. Chem. 269, 5493–5496). Also, plasmids containingthe Fab I gene from diazaborine resistant S. typhimurium conferreddiazaborine resistance in E. coli (Turnowsky, et al, (1989) J.Bacteriol., 171, 6555–6565). Furthermore, inhibition of Fab I either bydiazaborine or by raising the temperature in a Fab I temperaturesensitive mutant is lethal. These results demonstrate that Fab I isessential to the survival of the organism (Bergler, et al, (1994) J.Biol. Chem. 269, 5493–5496).

Recent studies have shown that Fab I is also the target for the broadspectrum antibacterial agent triclosan (McMurry, et al, (1998) Nature394, 531–532). A crystal structure of the E. Coli Fab I complexed withNAD and triclosan shows that triclosan acts as a site-directed, verypotent inhibitor of Fab I by mimicking its natural substrate (Levy, etal, (1999) Nature 398, 383–384). Ward, et al ((1999) Biochem. 38,12514–12525) have shown that there is no evidence for the formation of acovalent complex between Fab I and triclosan, which would be analogousto the diazaborines; triclosan differs from these compounds in that itis a reversible inhibitor of Fab I. The structural data for the complexof Fab I with NAD and triclosan provides important information about FabI as a therapeutic target.

Importantly, it has now been discovered that certain compounds are Fab Iinhibitors and have antibacterial activity, and, therefore, may beuseful for the treatment of bacterial infections in mammals,particularly in man.

SUMMARY OF THE INVENTION

This invention comprises compounds, as described hereinafter, whichinhibit Fab I and are useful in the treatment of bacterial infections.

This invention is also a pharmaceutical composition comprising compoundsof the instant invention according and a pharmaceutically acceptablecarrier.

This invention is a method of treating bacterial infections byinhibiting Fab I. In a particular aspect, the compounds of thisinvention are useful as antibacterial agents.

DETAILED DESCRIPTION

This invention comprises compounds of the formula (I):

wherein:

R¹ is H, C₁₋₄alkyl, —C₀₋₆alkyl-Ar, —(CH₂)₁₋₃N(R′)₂, or —(CH₂)₁₋₃OR′;

R² is H, C₁₋₄alkyl or C₃₋₆cycloalkyl;

R³ is

R⁴ is H or C₁₋₄alkyl;

indicates that one of the two designated bonds is a double bond and theother is a single bond;

R⁵ is CH₂ when the bond to which it is attached is a double bond; or R⁵is H or C₁₋₄alkyl when the bond to which it is attached is a singlebond;

R⁶ is H or C₁₋₄alkyl;

each R⁷ independently is H, C₁₋₆alkyl, —C₀₋₆alkyl-Ar, —(CH₂)₁₋₃N(R′)₂,or —(CH₂)₁₋₃OR′;

R⁸ is H or C₁₋₄alkyl;

R⁹ and R⁹′ independently are H or C₁₋₄alkyl;

R¹⁰ is C₁₋₄alkyl, N(R′)₂, NHC(O)R′, NHCH₂C(O)R′ or NHC(O)CH═CHR′;

Y* is N(R′)₂, NHC(O)R′, NHCH₂C(O)R′ or NHC(O)CH═CHR′;

each X independently is H, C₁₋₄alkyl, CH₂OH, OR′, SR′, CN, N(R′)₂,CH₂N(R′)₂, NO₂, CF₃, CO₂R′, CON(R′)₂, COR′, NR′C(O)R′, F, Cl, Br, I or—S(O)_(r)CF₃;

X* is —(CH₂)₁₋₃C(O)N(R′)—(CH₂)₁₋₃—Ar or —(CH₂)₁₋₃C(O)N(R′)—(CH₂)₁₋₃-Het;

W is S or O;

Q is H or C₁₋₄alkyl;

each R′ independently is H, C₁₋₆alkyl, —C₀₋₆alkyl-Ar or —C₀₋₆alkyl-Het;and

r is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

Additionally, this invention comprises compounds of formula (II):

wherein:

R¹ is H or C₁₋₄alkyl;

R² is H, C₁₋₄alkyl or C₃₋₆cycloalkyl;

R³ is

R⁴ is H or C₁₋₄alkyl;

indicates that one of the two designated bonds is a double bond and theother is a single bond;

R⁵ is CH₂ when the bond to which it is attached is a double bond; or R⁵is H or C₁₋₄alkyl when the bond to which it is attached is a singlebond;

R⁶ is H or C₁₋₄alkyl;

R⁷ is H, C₁₋₆alkyl or —C₀₋₆alkyl-Ar;

Y is H, C₁₋₄alkyl, N(R′)₂, NHC(O)R′, NHCH₂C(O)R′ or NHC(O)CH═CHR′;

each X independently is H, C₁₋₄alkyl, CH₂OH, OR′, SR′, CN, N(R′)₂,CH₂N(R′)₂, NO₂, CF₃, CO₂R′, CON(R′)₂, COR′, NR′C(O)R′, F, Cl, Br, I or—S(O)_(r)CF₃;

W is S or O;

Q is H or C₁₋₄alkyl;

M is CH₂ or O;

L is CH₂ or C(O);

E is O or NR′;

each R′ independently is H, C₁₋₆alkyl or —C₀₋₆alkyl-Ar; and

r is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

Also, this invention comprises compounds of formula (III):

wherein:

D¹ to D⁵ form an accessible substituted seven-membered ring, which maybe saturated or unsaturated, optionally containing up to two heteroatomschosen from the group of O, S and N wherein S and N may be optionallyoxidized;

R¹¹ is C₁₋₆alkyl; and

R″ is H or C₁₋₆alkyl;

or a pharmaceutically acceptable salt thereof.

This invention includes, but is not limited to, the following compounds:

(E)-3-(6-aminopyridin-3-yl)-N-(4,6-dichloro-1-methyl-1H-indol-2-ylmethyl)-N-methylacrylamide;

(E)-3-(2-aminopyrimidin-5-yl)-N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(1-ethyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(1-isopropyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-[6-(pyridin-2-ylamino)pyridin-3-yl]acrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(1,4-dimethyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(3,3-dimethyl-3H-indene-1-ylmethyl)-N-methylacrylamide;

(E)-3-(2-aminopyrimidin-5-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)acrylamide;

(E)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-methyl-N-(2-methylbenzo[b]thiophen-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylamide;

(E)-3-(3H-imidazo[4,5-b]pyridin-6-yl)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)acrylamide;

(E)-3-(3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-7-yl)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)acrylamide;

(E)-N-(1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(5-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(4-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(1H-indol-3-ylmethyl)-N-methylacrylamide

(E)-3-(6-aminopyridin-3-yl)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide;

(E)-3-(6-amino-5-(methoxycarbonyl)pyridin-3-yl)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-N-(1-benzyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(7-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylamide;

(E)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)acrylamide;

(E)-N-[1-(2-dimethylaminoethyl)-1H-indol-3-ylmethyl]-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-3-[6-amino-5-[[N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)amino]carbonylethyl]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide;

(E)-N-(2,3-dihydro-1H-3a-azacyclopenta[a]indene-8-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide;

(E)-N-(1-ethyl-5-fluoro-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(7-chloro-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(6-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-N-(5-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(6-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(7-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(7-hydroxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(6-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(5-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(4-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-N-methyl-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide;

(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide;

(E)-3-[6-[N-(carboxymethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide;

(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide;

(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methylacrylamide;

(E)-2,N-dimethyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-3-[6-[N-(carboxymethyl)amino]pyridin-3-yl]-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide;

(E)-3,N-dimethyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(4-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(5-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(7-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(7-methoxycarbonyl-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(7-fluoro-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)acrylamide;

(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(7-chloro-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(2-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-N-(2-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(5-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(4-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(6-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(4-fluoro-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(7-carboxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-N-(1,7-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(1,6-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(1,4-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(3,3-dimethyl-3H-indene-1-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(1,5-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(7-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(7-hydroxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

N-Methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e]-1,4-diazepin-7-yl)acrylamide;

(E)-N-[1-(2-hydroxyethyl)-1H-indol-3-ylmethyl]-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(4-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide;

(E)-N-(4-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(5-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(6-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(naphthalen-2-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(quinolin-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(6-amino-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(1-ethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(naphthalen-1-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-(benzofuran-2-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(6-methoxycarbonyl-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-[3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl]acrylamide;

(E)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-[6-(methoxycarbonyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]acrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(1,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-N-methylacrylamide;

(E)-N-(1,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)acrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)acrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)acrylamide;

(E)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-(benzofuran-3-ylmethyl)-N-methylacrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide;

(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(2-methylbenzofuran-3-ylmethyl)acrylamide;

(E)-N-(benzofuran-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-N-methyl-N-(2-methylbenzofuran-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

(E)-(6-aminopyridin-3-yl)-N-methyl-N-[1-(1-methyl-1H-indol-2-yl)ethyl]acrylamide;

(E)-(6-aminopyridin-3-yl)-N-methyl-N-[1-(1-methyl-1H-indol-3-yl)ethyl]acrylamide;

(E)-N-methyl-N-[1-(1-methyl-1H-indol-2-yl)ethyl]-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;and

(E)-N-methyl-N-[1-(1-methyl-1H-indol-3-yl)ethyl]-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

or a pharmaceutically acceptable salt thereof.

Also included in this invention are pharmaceutically acceptable additionsalts and complexes of the compounds of this invention. In cases whereinthe compounds of this invention may have one or more chiral centers,unless specified, this invention includes each unique racemic compound,as well as each unique nonracemic compound.

In cases in which compounds have unsaturated carbon-carbon double bonds,both the cis (Z) and trans (E) isomers are within the scope of thisinvention. In cases wherein compounds may exist in tautomeric forms,such as keto-enol tautomers, such as

and

each tautomeric form is contemplated as being included within thisinvention, whether existing in equilibrium or locked in one form byappropriate substitution with R′. The meaning of any substituent at anyone occurrence is independent of its meaning, or any other substituent'smeaning, at any other occurrence.

Also included in this invention are prodrugs of the compounds of thisinvention. Prodrugs are considered to be any covalently bonded carrierswhich release the active parent drug in vivo.

The compounds of this invention inhibit Fab I. Inhibition of this enzymeis useful in the treatment of bacterial infections. Also, the compoundsof this invention may be useful as antifungal agents. Additionally, thecompounds may be useful in combination with known antibiotics.

Abbreviations and symbols commonly used in the peptide and chemical artsare used herein to describe the compounds of this invention.

C₁₋₄alkyl as applied herein means an optionally substituted alkyl groupof 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl and t-butyl. C₁₋₆alkyl additionally includes pentyl,n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphaticisomers thereof. C₀₋₄alkyl and C₀₋₆alkyl additionally indicates that noalkyl group need be present (e.g., that a covalent bond is present).

Any C₁₋₄alkyl or C₁₋₆ alkyl may be optionally substituted with the groupR^(x), which may be on any carbon atom that results in a stablestructure and is available by conventional synthetic techniques.Suitable groups for R^(x) are C₁₋₄alkyl, OR′, SR′, CN, N(R′)₂,CH₂N(R′)₂, —NO₂, —CF₃, —CO₂R′—CON(R′)₂, —COR′, —NR′C(O)R′, F, Cl, Br, I,or —S(O)_(r)CF₃, wherein R′ and r are as defined for formula (I)compounds.

Halogen or halo means F, Cl, Br, and I.

Ar, or aryl, as applied herein, means phenyl or naphthyl, or phenyl ornaphthyl substituted by one to three substituents, such as those definedabove for alkyl, or substituted by methylenedioxy.

Het, or heterocycle, indicates an optionally substituted five or sixmembered monocyclic ring, or a nine or ten-membered bicyclic ringcontaining one to three heteroatoms chosen from the group of nitrogen,oxygen and sulfur, which are stable and available by conventionalchemical synthesis. Illustrative heterocycles are benzofuryl,benzimidazolyl, benzopyranyl, benzothienyl, furyl, imidazolyl,indolinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl,pyrrolidinyl, tetrahydropyridinyl, pyridinyl, thiazolyl, thienyl,quinolinyl, isoquinolinyl, and tetra- and perhydro-quinolinyl andisoquinolinyl. Any accessible combination of up to three substituents onthe Het ring, such as those defined above for alkyl, that are availableby chemical synthesis and are stable are within the scope of thisinvention.

Certain radical groups are abbreviated herein. t-Bu refers to thetertiary butyl radical, Boc refers to the t-butyloxycarbonyl radical,Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to thephenyl radical, Cbz refers to the benzyloxycarbonyl radical, Bn refersto the benzyl radical, Me refers to methyl, Et refers to ethyl, Acrefers to acetyl, Alk refers to C₁₋₄alkyl, Nph refers to 1- or2-naphthyl and cHex refers to cyclohexyl. Tet refers to 5-tetrazolyl.

Certain reagents are abbreviated herein. DCC refers todicyclohexylcarbodiimide, DMAP refers to dimethylaminopyridine, EDCrefers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride,HOBt refers to 1-hydroxybenzotriazole, THF refers to tetrahydrofuran,DIEA refers to diisopropylethylamine, DEAD refers to diethylazodicarboxylate, PPh₃ refers to triphenylphosphine, DIAD refers todiisopropyl azodicarboxylate, DME refers to dimethoxyethane, DMF refersto dimethylformamide, NBS refers to N-bromosuccinimide, Pd/C refers to apalladium on carbon catalyst, PPA refers to polyphosphoric acid, DPPArefers to diphenylphosphoryl azide, BOP refers tobenzotriazol-1-yloxy-tris(dimethyl-amino)phosphoniumhexafluorophosphate, HF refers to hydrofluoric acid, TEA refers totriethylamine, TFA refers to trifluoroacetic acid, PCC refers topyridinium chlorochromate.

In particular, compounds of this invention are prepared by the generalmethods described in the Schemes hereinafter:

A suitable haloaromatic derivative, for instance 2-amino-5-bromopyridine(I-1), reacts with an appropriate α,β-unsaturated ester, for examplebenzyl acrylate, in a Heck-type reaction (see Heck, Org. Reactions 1982,27, 345) to afford I-2. The reaction is mediated by a palladium(0)species, and generally is conducted in an inert solvent, such as CH₃CN,propionitrile, or toluene, in the presence of an appropriate acidscavenger, such as triethylamine (Et₃N) or diisopropylethylamine((i-Pr)₂NEt). Typical sources of the palladium(0) species includepalladium (II) acetate (Pd(OAc)₂) and palladium(II) chloride (PdCl₂),and oftentimes phosphine ligands, for instance triphenylphosphine (PPh₃)or tri-ortho-tolylphosphine (P(tol)3), are included. The ethyl ester ofI-2 is hydrolyzed using aqueous base, for example, LiOH in aqueous THFor NaOH in aqueous methanol or ethanol, and the intermediate carboxylatesalt is acidified with a suitable acid, for instance TFA or HCl, toafford the carboxylic acid I-3. The carboxylic acid of I-3 is convertedto an activated form using, for example, EDC and HOBt, or SOCl₂, and theactivated form is subsequently reacted with an appropriate amine, forinstance 1-methyl-2-(methylaminomethyl)indole, in a suitable solventsuch as DMF, CH₂Cl₂, or CH₃CN, to afford I-4. Depending on whether acidneutralization is required, an added base, such as triethylamine (Et₃N),diisopropylethylamine ((i-Pr)₂NEt), or pyridine, may be used. Manyadditional methods for converting a carboxylic acid to an amide areknown, and can be found in standard reference books, such as “Compendiumof Organic Synthetic Methods”, Vol. I–VI (published byWiley-Interscience), or Bodansky, “The Practice of Peptide Synthesis”(published by Springer-Verlag).

The amine coupling partners used in the present invention were preparedby established methods well-known to those of skill in the art. Forexample, amine II-4 is prepared by the straightforward procedureoutlined in Scheme II. Commercially available ethyl indole-2-carboxylate(II-1) is deprotonated with a suitable base, generally sodium hydride(NaH), and the intermediate sodium salt is reacted with an appropriatealkylating agent, for instance methyl iodide, to afford II-2. Polarsolvents such as DMF, THF, or mixtures thereof are generally preferredfor this reaction. Compound II-2 can be conveniently converted to II-3by reaction with an excess of an amine, such as methylamine, in a polarsolvent, generally H₂O or a mixture of H₂O and methanol. Alternatively,the ester of II-2 can be saponified under standard conditions, typicallywith an alkali metal hydroxide such as LiOH, NaOH, or KOH, in an aqueoussolvent, such as THF, ethanol, or methanol, and the resulting carboxylicacid can be converted to the desired amide. Typical methods for formingamides are described in Scheme I. Reduction of the amide II-3 to theamine II-4 is typically accomplished with lithium aluminum hydride(LiAlH₄) in refluxing THF, although many other methods can be used toreduce amides to amines. Such methods are well-known to those of skillin the art, and can be found in standard reference volumes, such as“Compendium of Organic Synthetic Methods” (published byWiley-Interscience).

The amine coupling partners used in the present invention can also beprepared by the reductive amination of an appropriate aldehyde (SchemeIII). This method, which is well-known to those of skill in the art,involves the initial conversion of an aldehyde to an intermediate imine,which is subsequently reduced, oftentimes in situ, to afford the amine.For example, the commercially-available aldehyde III-1 reacts with anappropriate amine, for instance methylamine, in a suitable solvent,typically methanol, to afford the imine III-2. Reaction of III-2 with asuitable reducing agent, for example sodium borohydride, sodiumcyanoborohydride or sodium (triacetoxy)borohydride, gives the amineIII-3.

Commercially available 2-aminonicotinic acid (IV-1) is reduced toalcohol IV-2 under standard conditions (LiAlH₄, THF), and the aromaticring of IV-2 is brominated using, for example, bromine orN-bromosuccinimide (NBS), in a suitable solvent such as CH₂Cl₂, aceticacid (AcOH), or mixtures thereof, to afford IV-3. On reaction with 48%aqueous HBr, IV-3 is converted to bromide IV-4, which reacts with adiester of malonic acid, for instance dimethyl malonate, under basicconditions, to afford the naphthyridone derivative IV-5. Typical basicconditions include an alkali metal hydride, for instance sodium hydride,in a neutral solvent such as DMF, THF, or mixtures thereof, or an alkalimetal alkoxide, such as sodium methoxide or sodium ethoxide, in analcoholic solvent such as with methanol or ethanol. Saponification andneutralization under standard conditions affords an intermediatecarboxylic acid (not shown), which is typically not isolated, but issubject to decarboxylation on gentle warming to afford the naphthyridoneIV-6. This compound reacts with acrylamide IV-8 in a Heck-type reactionas described in Scheme I to afford IV-9. Alternatively, IV-6 might beconverted to IV-9 according to the general procedure described in SchemeI for the conversion of I-1 to I-4. The acrylamide IV-8 is convenientlyprepared by reaction of amine IV-7 (see Scheme I) with an activated formof acrylic acid in an amide bond-forming reaction. Typical conditionsfor the formation of amides are described in Scheme I, and arewell-known to those of skill in the art.

Benzylic bromide V-1, prepared as described in Scheme IV, reacts with anamine, for example aqueous methylamine, to afford benzylic amine V-2.Polar solvents such as THF, DMF, DMSO, or mixture thereof, are generallypreferred for this reaction. V-2 reacts with a dialkyl carbonate,preferably dimethyl carbonate, in the presence of a suitable base,typically sodium methoxide, in an alcoholic solvent, generally methanol,to afford the cyclic urea derivative V-3. This compound is converted toV-4 by reaction with compound IV-8 as described in Scheme IV.

The nitro group of commercially available2-amino-5-bromo-3-nitropyridine (VI-1) is reduced under standardconditions using, for example, tin (II) chloride in EtOH. The resultingdiamine, VI-2, reacts with formic acid, or an appropriate equivalent, toafford the imidazopyridine derivative VI-3. This compound is convertedto a suitably protected derivative, for instance the N-trityl protectedderivative VI-4, by reaction with trityl chloride in the presence of anappropriate base, typically triethylamine or diisopropylethylamine.Typical solvents for this reaction include CH₂Cl₂, DMF, or mixturesthereof. The protecting group for the amine must be compatible withsubsequent chemistry, and must be readily removable when desired.Methods for the protection of amines are well-known to those of skill inthe art, and are described in standard reference volumes, such as Greene“Protective Groups in Organic Synthesis” (published byWiley-Interscience). VI-4 is converted to VI-5 according to the generalprocedure described in Scheme I. The trityl protecting group is removedunder standard acidic conditions (see Greene above), and the ester issaponified as in Scheme I to afford VI-6.

Commercially-available tetrahydroquinoline (VII-1) is condensed with anappropriate aldehyde, typically benzaldehyde (PhCHO), under standardconditions to afford the olefinic derivative VII-2. Oxidative cleavageof the exocyclic olefin affords ketone VII-3. Generally, ozonolysis in aneutral solvent, such as methylene chloride (CH₂Cl₂), methanol (MeOH),or mixtures thereof, followed by in situ reduction of the intermediateozonide with an appropriate reducing agent, usually dimethylsulfide, isthe method of choice for this transformation. Compound VII-3 isconverted to the 7-membered lactam derivative VII-6 as described byJössang-Yanagida and Gansser (J. Het. Chem. 1978, 15, 249–251). Thisprocedure involves conversion of the ketone of VII-3 to thecorresponding oxime VII-4, which is subsequently converted to theO-tosyl derivative VII-5. A Beckmann-type rearrangement of VII-5 affordsthe lactam VII-6. Bromination of VII-6 with a suitable brominatingagent, such as bromine (Br₂) or N-bromosuccinimide (NBS), affords thebromo derivative VII-7. Typical solvents for a bromination reactioninclude CH₂Cl₂, CCl₄, MeOH, AcOH, or mixtures thereof. Bromide VII-7reacts with an appropriate α,β-unsaturated ester, for example tert-butylacrylate, in a Heck-type reaction as described in Scheme I to affordVII-8. The tert-butyl ester of VII-8 is cleaved to the correspondingcarboxylic acid VII-9 under standard acidic conditions. Typicalconditions for this transformation are described in standard referencevolumes, such as Greene “Protective Groups in Organic Synthesis”(published by Wiley-Interscience). VII-9 is converted to VII-10 by thegeneral method described in Scheme I.

Compound VIII-1, prepared as described in Scheme V, reacts with twoequivalents of an appropriate acylating agent, preferably di-tert-butyldicarbonate, to afford VIII-2. As discussed in Scheme VI, the protectinggroup for the amines must be compatible with subsequent chemistry, andmust be readily removable when desired. VIII-2 is deprotonated with asuitable base, generally sodium hydride (NaH), and the intermediatesodium salt is reacted with an appropriate alkylating agent, forinstance ethyl bromoacetate, to afford VIII-3. Polar solvents such asDMF, THF, or mixtures thereof are generally preferred for this reaction.The Boc protecting groups are removed under standard acidic conditions(see Greene above) to afford VIII-4, which undergoes cyclization tocompound VIII-5 on exposure to a suitable base, typically triethylamine(Et₃N) or diisopropylethylamine ((i-Pr)₂NEt). An inert solvent, such astoluene, is preferred. VIII-5 is converted to VIII-6 by the generalmethod described in Scheme IV.

Commercially available 2,5-dibromopyridine (IX-1) reacts with2-aminopyridine in the presence of a suitable base, typically sodiumtert-butoxide, to afford the dipyridylamine derivative IX-2. Thereaction is mediated by a suitable palladium (0) catalyst, such astris(dibenzylideneacetone)dipalladium(0), in the presence of anappropriate ligand, for example 1,3-bis(diphenylphosphino)propane. Aneutral solvent such as toluene is preferred.

Benzylic bromide V-1, prepared as described in Scheme IV, reacts with anappropriate a-aminoester equivalent, for exampleN-(diphenylmethylene)glycine ethyl ester, under basic conditions, toprovide X-2. A polar, aprotic solvent, such as DMF, THF, DME, ormixtures thereof, is generally preferred, and sodium hydride istypically the base of choice, although LDA or LiN(TMS)₂ might also beused. Alternatively, the reaction might be conducted in an alcoholicsolvent, such as methanol or ethanol, with an alkali metal alkoxide, forexample sodium methoxide or sodium ethoxide, as the base. Thediphenylmethylene group is conveniently removed under acidic conditions,such as HCl in aqueous dioxane. Other conditions for the removal of adiphenylmethylene group are known to those of skill in the art, and canbe found in the chemical literature or in standard reference volumes,such as Greene (see above).

Acid addition salts of the compounds are prepared in a standard mannerin a suitable solvent from the parent compound and an excess of an acid,such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric,acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain ofthe compounds form inner salts or zwitterions which may be acceptable.Cationic salts are prepared by treating the parent compound with anexcess of an alkaline reagent, such as a hydroxide, carbonate oralkoxide, containing the appropriate cation; or with an appropriateorganic amine. Cations such as Li⁺, Na⁺, K⁺, Ca⁺⁺, Mg⁺⁺ and NH₄ ⁺ arespecific examples of cations present in pharmaceutically acceptablesalts.

This invention also provides a pharmaceutical composition whichcomprises a compound according to the instant invention and apharmaceutically acceptable carrier. Accordingly, the compounds of thepresent invention may be used in the manufacture of a medicament.Pharmaceutical compositions of the compounds of this invention preparedas hereinbefore described may be formulated as solutions or lyophilizedpowders for parenteral administration. Powders may be reconstituted byaddition of a suitable diluent or other pharmaceutically acceptablecarrier prior to use. The liquid formulation may be a buffered,isotonic, aqueous solution. Examples of suitable diluents are normalisotonic saline solution, standard 5% dextrose in water or bufferedsodium or ammonium acetate solution. Such formulation is especiallysuitable for parenteral administration, but may also be used for oraladministration or contained in a metered dose inhaler or nebulizer forinsufflation. It may be desirable to add excipients such aspolyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethyleneglycol, mannitol, sodium chloride or sodium citrate.

Alternately, these compounds may be encapsulated, tableted or preparedin a emulsion or syrup for oral administration. Pharmaceuticallyacceptable solid or liquid carriers may be added to enhance or stabilizethe composition, or to facilitate preparation of the composition. Solidcarriers include starch, lactose, calcium sulfate dihydrate, terra alba,magnesium stearate or stearic acid, talc, pectin, acacia, agar orgelatin. Liquid carriers include syrup, peanut oil, olive oil, salineand water. The carrier may also include a sustained release materialsuch as glyceryl monostearate or glyceryl distearate, alone or with awax. The amount of solid carrier varies but, preferably, will be betweenabout 20 mg to about 1 g per dosage unit. The pharmaceuticalpreparations are made following the conventional techniques of pharmacyinvolving milling, mixing, granulating, and compressing, when necessary,for tablet forms; or milling, mixing and filling for hard gelatincapsule forms. When a liquid carrier is used, the preparation will be inthe form of a syrup, elixir, emulsion or an aqueous or non-aqueoussuspension. Such a liquid formulation may be administered directly p.o.or filled into a soft gelatin capsule.

For rectal administration, the compounds of this invention may also becombined with excipients, such as cocoa butter, glycerin, gelatin orpolyethylene glycols, and molded into a suppository.

For topical administration, the compounds of this invention may becombined with diluents to take the form of ointments, gels, pastes,creams, powders or sprays. The compositions which are ointments, gels,pastes or creams contain diluents, for example, animal and vegetablefats, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures of these substances. The compositions which arepowders or sprays contain diluents, for example, lactose, talc, silicicacid, aluminum hydroxide, calcium silicate and polyamide powder, ormixtures of these substances. Additionally, for topical ophthalmologicadministration, the typical carriers are water, mixtures of water andwater miscible solvents, such as lower alkanols or vegetable oils, andwater-soluble non-toxic polymers, for example cellulose derivatives,such as methyl cellulose.

The compounds described herein are inhibitors of Fab I, and are usefulfor treating bacterial infections. For instance, these compounds areuseful for the treatment of bacterial infections, such as, for example,infections of upper respiratory tract (e.g. otitis media, bacterialtracheitis, acute epiglottitis, thyroiditis), lower respiratory (e.g.empyema, lung abscess), cardiac (e.g. infective endocarditis),gastrointestinal (e.g. secretory diarrhoea, splenic abscess,retroperitoneal abscess), CNS (e.g. cerebral abscess), eye (e.g.blepharitis, conjunctivitis, keratitis, endophthalmitis, preseptal andorbital cellulitis, darcryocystitis), kidney and urinary tract (e.g.epididymitis, intrarenal and perinephric abscess, toxic shock syndrome),skin (e.g. impetigo, folliculitis, cutaneous abscesses, cellulitis,wound infection, bacterial myositis), and bone and joint (e.g. septicarthritis, osteomyelitis). Also, the compounds of this invention may beuseful as antifungal agents. Additionally, the compounds may be usefulin combination with known antibiotics.

The compounds of this invention are administered to the patient, in amanner such that the concentration of drug is sufficient to treatbacterial infections. The pharmaceutical composition containing thecompound is administered at an oral dose of between about 10 mg to about1000 mg, taken once or several times daily, in a manner consistent withthe condition of the patient. Preferably, the oral dose would be about50 mg to about 500 mg, although the dose may be varied depending uponthe age, body weight and symptoms of the patient. For acute therapy,parenteral administration is preferred. An intravenous infusion of thecompound of formula (I) in 5% dextrose in water or normal saline, or asimilar formulation with suitable excipients, is most effective,although an intramuscular bolus injection is also useful. The preciselevel and method by which the compounds are administered is readilydetermined by one skilled in the art.

The compounds may be tested in one of several biological assays todetermine the concentration of compound which is required to have agiven pharmacological effect.

Cloning of S. aureus FabI

The fabI gene was cloned from the chromosomal DNA of S. aureus strainWCUH29 using the polymerase chain reaction. Amplification was performedusing Taq DNA polymerase (BRL) and the following primers:5′-CGCCTCGAGATGTTAAATCTTGAAAACAAAACATATGTC-3′ and5′-CGCGGATCCAATCAAGTCAGGTTGAAATATCCA-3′ (XhoI and BamHI sitesunderlined). The resulting fragment was then digested with XhoI andBamHI and ligated into XhoI- and BamHI-digested expression vectorpET-16b (Novagen), producing pET-His₁₀-fabI. The gene sequence of fabIwas confirmed by automated cycle sequencing using an Applied Biosystemsmodel 377 machine. The untagged version of pET-fabI was constructed bydigesting pET-His₁₀-fabI with NcoI and NdeI to remove a 97 bp fragmentencoding the His 10 tag, the factor Xa cleavage site and the first 8amino acids of FabI, and replacing it with a linker encoding the first 8amino acids of FabI plus a glycine residue between the initiatormethionine and the lysine at position 2. This plasmid was calledpET-fabI. The linker was made by annealing the following twooligonucleotides: 5′-CATGGGCTTAAATCTTGAAAACAAAACA-3′ and5′-TATGTTTTGTTTTCAAGATTTAAGCC-3′. The linker sequence in pET-fabI wasconfirmed by dideoxy sequencing. Only native FabI was used for compoundevaluation. For overproduction of native FabI, plasmid pET-fabI wastransformed into BL21(DE3) (Novagen) cells, to form strainBL21(DE3):pET-fabI.

Purification of S. aureus FabI

S. aureus FabI was expressed as soluble protein to 10% of total cellprotein, 400 g cells being recovered from 15 L fermentation in tryptonephosphate medium. The cells were lysed and the sample centrifuged. Theresulting supernatant was filtered and purified using three consecutivechromatography columns: ion-exchange (Sourse 15Q), dye-affinity (Bluesepharose), and size exclusion chromatography columns (Superose 12).After each column the FabI containing fractions were pooled,concentrated, and checked for purity and biological activity.

Cloning/Expression Haemophilus influenzae FabI

The FabI gene was PCR amplified from Haemophilus influenzae (Q1) genomicDNA. Oligonucleotide primers were designed with unique restriction sitesat both the N′ and C′ terminal ends of the gene to allow efficientsub-cloning into the expression vector pPROLar.

FORWARD PRIMER KpnI 5′GCGGTACCCATGCGCTTGGTTTTCTTAGAAATATTG′3 REVERSEPRIMER NotI 5′GCGGCCGCTTATTCTTCGCCTAATTCGCCCATTGC′3

PCR amplification was performed using Pfu Turbo DNA polymerase as perthe instructions of the manufacturer (Stratagene). The following cyclingconditions were used: 95° C. for 3 minutes followed by 30 cycles of 94°C. 1 minute, 55° C. 1 minute and 72° C. 3 minutes. A final extension at72° C. for 5 minutes was carried out. PCR products of expected size forHaemophilus influenzae FabI were cloned into the PCR cloning vector TOPOTA 2.1 as per instructions of the manufacturer (Invitrogen). Thefidelity of the presumptive PCR amplified Haemophilus influenzae FabIgene was confirmed by DNA sequencing on both strands using an ABI 377Automative DNA Sequencer (Applied Biosystems). pPROLar was digested withKpnI and NotI restriction endonucleases using conditions as recommendedby the supplier (New England Biolabs). Purification of the linearplasmid, was achieved using agarose gel purification and the Qia-quickgel purification kit as per the protocol supplied by the manufacturer(Qiagen). The Haemophilus influenzae FabI gene was excised from TOPO TA2.1 by KpnI and NotI restriction endonuclease digestion and purified asabove. Subsequent fragment/vector ligations were carried out using T4DNA ligase, using conditions supplied by the manufacturer (Promega).

Transformations into E. coli TOP 10 competent cells were performed usingthe protocol as supplied by the manufacturer (Invitrogen). Verificationof the resultant clones was carried out using colony PCR and restrictionendonuclease digestion. Positive clones were then transformed into theexpression strain E. coli DH5.PRO, which expresses AraC in addition tothe lac repressor.

Subsequent clones were then evaluated for expression at small-scaleusing the conditions as recommended by the manufacturer (Clontech).Expression analysis showed over-expressed protein bands of correct sizefor Haemophilus influenzae FabI clearly visible by SDS PAGE. Proteinidentity was further confirmed by peptide mass fingerprinting. Furtheranalysis by N-terminal Amino Acid sequencing of the purified proteinshowed that the N-terminus starts 35 residues downstream of thepresumptive initiation codon. DNA sequence analysis also highlighted thepresence of a ribosome binding site upstream and correctly spaced fromthe new initiation codon. These findings match perfectly with E. coliFabI and the protein is also now a similar size to other FabIs. Theover-expression construct has managed to use the correct ribosomebinding site and start at the correct ATG to give the correct protein.

Purification of H. influenzae FabI

One liter of cells containing the H. influenzae FabI expressionconstruct were grown to an OD600 of 0.6. Expression was induced asdescribed above and the cells were grown for a further 3 h and thenharvested. The cell pellet was re-suspended in 10 ml 50 mM Tris pH 7.5,1 mM PMSF, 1 mM benzamidine, 1 mM DTT (buffer A) and lysed bysonication. Cell debris was removed by centrifugation. The supernatantwas loaded onto a Hi-load Q (16/10) column (Pharmacia) equilibrated inbuffer A. Protein was eluted over a 200 mL gradient of 0–100% buffer B,where buffer B is buffer A+1 M KCl. Fractions containing FabI wereidentified by SDS PAGE and by their FabI activity and pooled.

1.5 M ammonium sulfate was added to the pooled fractions and these werethen loaded onto a Hi-load phenyl sepharose (16/10) column (Pharmacia)equilibrated in 50 mM Tris pH 7.5, 1 mM PMSF, 1 mM benzamidine, 1 mMDTT, 1.5 M ammonium sulfate. Proteins were eluted with a gradient ofammonium sulfate (1.5 to 0 M) over 200 mL. Fractions containing FabIwere identified as above and pooled. The pooled fractions were bufferexchanged into 100 mM Tris, pH 7.5, 2 mM DTT and glycerol was then addedto 50%. The protein was stored at −20° C. The identity of the proteinwas confirmed by N-terminal sequencing and MALDI mass spectrometry.

Cloning of E. coli FabI

A PCR fragment of correct size for E. coli FabI was PCR amplified fromE. coli chromosomal DNA, subcloned into the TOPO TA cloning vector, andverified by colony PCR+restriction endonuclease analysis. Thepresumptive E. coli FabI PCR fragment was subcloned into the expressionvector pBluePet. The FabI clone was transformed into E. coli strainBL21(DE3). Small Scale expression studies show an over-expressed proteinband of correct molecular weight (˜28 Kda) for E. coli FabI clearlyvisible following Coomassie staining of SDS PAGE gels. DNA sequencing ofthe E. coli FabI expression constructs illustrated that no errors wereapparent. N′ terminal amino acid sequencing has confirmed theover-expressed protein band to be E. coli FabI.

Purification of E. coli FabI

E. coli FabI was expressed as soluble protein to 15% of total cellprotein, 120 g cells being recovered from 3 L fermentation in shakeflasks in modified terrific broth. The cells were lysed and the samplecentrifuged. The resulting supernatant was filtered and purified usingthree consecutive chromatography columns: ion-exchange (Sourse 15Q),dye-affinity (blue sepharose), and size exclusion (superose 12). Aftereach column the FabI containing fractions were pooled, concentrated andchecked for purity and biological activity.

S aureus FabI Enzyme Inhibition Assay (NADH)

Assays were carried out in half-area, 96-well microtitre plates.Compounds were evaluated in 50-uL assay mixtures containing 100 mMNaADA, pH 6.5 (ADA=N-[2-acetamido]-2-iminodiacetic acid), 4% glycerol,0.25 mM crotonoyl CoA, 1 mM NADH, and an appropriate dilution of S.aureus FabI. Inhibitors were typically varied over the range of 0.01–10uM. The consumption of NADH was monitored for 20 minutes at 30° C. byfollowing the change in absorbance at 340 nm. Initial velocities wereestimated from an exponential fit of the non-linear progress curvesrepresented by the slope of the tangent at t=0 min. IC₅₀'s wereestimated from a fit of the initial velocities to a standard,4-parameter model and are typically reported as the mean ±S.D. ofduplicate determinations. Triclosan, a commercial antibacterial agentand inhibitor of FabI, is currently included in all assays as a positivecontrol. Compounds of this invention have IC₅₀'s from about 5.0micromolar to about 0.05 micromolar.

S aureus FabI Enzyme Inhibition Assay (NADPH)

Assays were carried out in half-area, 96-well microtitre plates.Compounds were evaluated in 150-uL assay mixtures containing 100 mMNaADA, pH 6.5 (ADA=N-[2-acetamido]-2-iminodiacetic acid), 4% glycerol,0.25 mM crotonoyl CoA, 50 uM NADPH, and an appropriate dilution of S.aureus FabI. Inhibitors were typically varied over the range of 0.01–10uM. The consumption of NADPH was monitored for 20 minutes at 30° C. byfollowing the change in absorbance at 340 nm. Initial velocities wereestimated from an exponential fit of the non-linear progress curvesrepresented by the slope of the tangent at t=0 min. IC₅₀'s wereestimated from a fit of the initial velocities to a standard,4-parameter model and are typically reported as the mean ±S.D. ofduplicate determinations. Triclosan, a commercial antibacterial agentand inhibitor of FabI, is currently included in all assays as a positivecontrol.

H. influenzae FabI Enzyme Inhibition Assay

Assays are carried out in half-area, 96-well microtiter plates.Compounds are evaluated in 150-uL assay mixtures containing 100 mM MES,51 mM diethanolamine, 51 mM triethanolamine, pH 6.5(MES=2-(N-morpholino)ethanesulfonic acid), 4% glycerol, 25 uMcrotonoyl-ACP, 50 uM NADH, and an appropriate dilution of H. influenzaeFabI (approximately 20 nM). Inhibitors are typically varied over therange of 0.01–10 uM. The consumption of NADH is monitored for 20 minutesat 30° C. by following the change in absorbance at 340 nm. Initialvelocities are estimated from an exponential fit of the non-linearprogress curves. IC50's are estimated from a fit of the initialvelocities to a standard, 4-parameter model, and are typically reportedas the mean ±S.D. of duplicate determinations. The apparent Ki iscalculated assuming the inhibition is competitive with crotonoyl-ACP. Aproprietary lead compound is currently included in all assays as apositive control.

E. coli FabI Enzyme Inhibition Assay

Assays were carried out in half-area, 96-well microtitre plates.Compounds were evaluated in 150-uL assay mixtures containing 100 mMNaADA, pH 6.5 (ADA=N-[2-acetamido]-2-iminodiacetic acid), 4% glycerol,0.25 mM crotonoyl CoA, 50 uM NADH, and an appropriate dilution of E.coli FabI. Inhibitors were typically varied over the range of 0.01–10uM. The consumption of NADH was monitored for 20 minutes at 30° C. byfollowing the change in absorbance at 340 nm. Initial velocities wereestimated from an exponential fit of the non-linear progress curvesrepresented by the slope of the tangent at t=0 min. IC₅₀'s wereestimated from a fit of the initial velocities to a standard,4-parameter model and are typically reported as the mean ±S.D. ofduplicate determinations. Triclosan, a commercial antibacterial agentand inhibitor of FabI, is currently included in all assays as a positivecontrol. Compounds of this invention have IC₅₀'s from about 100.0micromolar to about 0.05 micromolar.

Preparation and Purification of Crotonoyl-ACP

Reactions contained 5 mg/mL E. coli apo-ACP, 0.8 mM crotonoyl-CoA(Fluka), 10 mM MgCl₂, and 30 uM S. pneumoniae ACP synthase in 50 mMNaHEPES, pH 7.5. The mixture was gently mixed on a magnetic stirrer at23° C. for 2 hr, and the reaction was terminated by the addition of 15mM EDTA. The reaction mixture was filtered through a 0.2 micron filter(Millipore) and applied to a MonoQ column (Pharmacia) equilibrated with20 mM Tris-Cl, pH 7.5. The column was washed with buffer until allnon-adherent material was removed (as observed by UV detection), and thecrotonoyl-ACP was eluted with a linear gradient of 0 to 400 mM NaCl.

S. aureus FabI Enzyme Inhibition Assay Using Crotonoyl-ACP

Assays are carried out in half-area, 96-well microtitre plates.Compounds are evaluated in 150 uL assay mixtures containing 100 mMNaADA, pH 6.5 (ADA=N-(2-acetamido)-2-iminodiacetic acid), 4% glycerol,25 uM crotonoyl-ACP, 50 uM NADPH, and an appropriate dilution of S.aureus Fab I (approximately 20 nM). Inhibitors are typically varied overthe range of 0.01–10 uM. The consumption of NADPH is monitored for 20minutes at 30° C. by following the change in absorbance at 340 nm.Initial velocities are estimated from a linear fit of the progresscurves. IC50's are estimated from a fit of the initial velocities to astandard, 4-parameter model (Equation 1) and are typically reported asthe mean ±S.D. of duplicate determinations. Compounds of this inventionin this assay have IC₅₀'s from about 100.0 micromolar to about 0.04micromolar. The apparent Ki is calculated from Equation 2 assuming theinhibition is competitve with crotonoyl-ACP.v=Range/(1+[I]/IC50)s+Background  Equation 1:Ki(app)=IC50/(1+[S]/Ks)  Equation 2:Antimicrobial Activity Assay

Whole-cell antimicrobial activity was determined by broth microdilutionusing the National Committee for Clinical Laboratory Standards (NCCLS)recommended procedure, Document M7-A4, “Methods for DilutionSusceptibility Tests for Bacteria that Grow Aerobically”. The compoundwas tested in serial two-fold dilutions ranging from 0.06 to 64 mcg/mL.Test organisms were selected from the following laboratory strains:Staphylococcus aureus Oxford, Staphylococcus aureus WCUH29,Streptococcus pneumoniae ERY2, Streptococcus pneumoniae 1629,Streptococcus pneumoniae N 1387, Enterococcus faecalis 1, Enterococcusfaecalis 7, Haemophilus influenzae Q1, Haemophilus influenzae NEMCl,Moraxella Catarrhalis 1502, Escherichia coli 7623 AcrABEFD+, Escherichiacoli 120 AcrAB-, Escherichia coli MG1655, Escherichia coli MG1658. Theminimum inhibitory concentration (MIC) was determined as the lowestconcentration of compound that inhibited visible growth. A mirror readerwas used to assist in determining the MIC endpoint.

One skilled in the art would consider any compound with a MIC of lessthan 256 μg/mL to be a potential lead compound. Preferably, thecompounds used in the antimicrobial assays of the present invention havea MIC value of less than 128 μg/mL. Most preferably, said compounds havea MIC value of less than 64 μg/mL.

The examples which follow are intended in no way to limit the scope ofthis invention, but are provided to illustrate how to make and use thecompounds of this invention. Many other embodiments will be readilyapparent to those skilled in the art.

EXAMPLES General

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded ateither 300 or 400 MHz, and chemical shifts are reported in parts permillion (δ) downfield from the internal standard tetramethylsilane(TMS). Abbreviations for NMR data are as follows: s=singlet, d=doublet,t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet oftriplets, app=apparent, br=broad. J indicates the NMR coupling constantmeasured in Hertz. CDCl₃ is deuteriochloroform, DMSO-d₆ ishexadeuteriodimethylsulfoxide, and CD₃OD is tetradeuteriomethanol. Massspectra were obtained using electrospray (ES) ionization techniques.Elemental analyses were performed by Quantitative Technologies Inc.,Whitehouse, N.J. Melting points were obtained on a Thomas-Hoover meltingpoint apparatus and are uncorrected. All temperatures are reported indegrees Celsius. Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254thin layer plates were used for thin layer chromatography. Flashchromatography was carried out on E. Merck Kieselgel 60 (230–400 mesh)silica gel. Analytical HPLC was performed on Beckman chromatographysystems. Preparative HPLC was performed using Gilson chromatographysystems. ODS refers to an octadecylsilyl derivatized silica gelchromatographic support. YMC ODS-AQ® is an ODS chromatographic supportand is a registered trademark of YMC Co. Ltd., Kyoto, Japan. PRP-1® is apolymeric (styrene-divinylbenzene) chromatographic support, and is aregistered trademark of Hamilton Co., Reno, Nev. Celite® is a filter aidcomposed of acid-washed diatomaceous silica, and is a registeredtrademark of Manville Corp., Denver, Colo.

Preparation 1 Preparation of (E)-3-(6-aminopyridin-3-yl)acrylic acid(Method A)

a) Benzyl (E)-3-(6-aminopyridin-3-yl)acrylate

A solution of 2-amino-5-bromopyridine (2.25 g, 13.0 mmole), benzylacrylate (3.2 g, 19.7 mmole), Pd(OAc)₂ (0.31 g, 1.4 mmole),tri-ortho-tolylphosphine (0.73 g, 2.4 mmole), and diisopropylethylamine(3.5 mL, 20.0 mmole) in propionitrile (50 mL) was heated at refluxovernight. The dark mixture was filtered through celite®, and thefiltrate was concentrated. Flash chromatography on silica gel (3%MeOH/CH₂Cl₂) gave the title compound (1.3 g, 39%): MS (ES) m/e 255(M+H)⁺.

b) (E)-3-(6-Aminopyridin-3-yl)acrylic acid

A solution of benzyl (E)-3-(6-aminopyridin-3-yl)acrylate (1.3 g, 5.1mmole) and 1.0 N NaOH (10 mL, 10 mmole) in MeOH was heated at refluxovernight. The solution was concentrated in vacuo, and the residue wasdissolved in H₂O. The pH was adjusted to 6 with dilute HCl, and thesolid precipitate was collected by suction filtration and dried to givethe title compound (0.6 g, 72%) as a white solid: MS (ES) m/e 165(M+H)⁺.

Preparation 2 Preparation of (E)-3-(6-aminopyridin-3-yl)acrylic acid(Method B)

a) (E)-3-(6-Aminopyridin-3-yl)acrylic acid

Acrylic acid (23 mL, 0.33 mole) was added carefully to a solution of2-amino-5-bromopyridine (25.92 g, 0.15 mole) and Na₂CO₃ (55.64 g, 0.53mole) in H₂O (600 mL). PdCl₂ (0.53 g, 0.003 mole) was then added, andthe mixture was heated at reflux. After 24 hr, the reaction was cooledto RT and filtered, and the filtrate was adjusted to pH 6 with aqueousHCl. Additional H₂O (0.5 L) was added to improve mixing, and the mixturewas stirred for 1 hr. The pH was readjusted to 6, then the solid wascollected by suction filtration. The filter pad was washed sequentiallywith H₂O (2×0.5 L), cold absolute EtOH (100 mL), and Et₂O (2×250 mL).Drying in high vacuum at elevated temperature gave the title compound(15.38 g, 62%) as a tan solid: 1H NMR (300 MHz, DMSO-d₆) δ 8.11 (d,J=2.0 Hz, 1 H), 7.75 (dd, J=8.7, 2.0 Hz, 1 H), 7.43 (d, J=15.8 Hz, 1 H),6.53 (s, 2 H), 6.45 (d, J=8.7 Hz, 1 H), 6.22 (d, J=15.8 Hz, 1 H); MS(ES) m/e 165 (M+H)⁺.

Preparation 3 Preparation of (E)-3-(2-aminopyrimidin-5-yl)acrylic acid

a) Benzyl (E)-3-(2-aminopyrimidin-5-yl)acrylate

According to the procedure of Preparation 1(a), except substituting5-bromo-2-aminopyrimidine (1.95 g, 11.2 mmole) for2-amino-5-bromopyridine, the title compound (2.25 g, 79%) was preparedas a light orange solid: MS (ES) m/e 256 (M+H)⁺.

b) (E)-3-(2-Aminopyrimidin-5-yl)acrylic acid

According to the procedure of Preparation 1(b), except substitutingbenzyl (E)-3-(2-aminopyrimidin-5-yl)acrylate (2.93 g, 11.5 mmole) forbenzyl (E)-3-(6-aminopyridin-3-yl)acrylate, the title compound (1.71 g,90%) was prepared as an off-white solid: MS (ES) m/e 166 (M+H)⁺.

Preparation 4 Preparation of6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one

a) 2-Amino-3-(hydroxymethyl)pyridine

Solid 2-aminonicotinic acid (199 g, 1.44 mole) was added in portionsover 4 hr to 1.0 M LiAlH₄ in THF (3 L, 3 mole) with stirring underArgon. An ice-bath was applied to control the temperature below 30° C.After the addition was complete, the reaction was heated at reflux for16 hr, then was cooled to 0° C. and carefully quenched by sequentialaddition of H₂O (120 mL), 15% NaOH in H₂O (120 mL), and H₂O (350 mL).The resulting thick suspension was stirred for 1 hr, then was filteredthrough a pad of celite®. The filter pad was rinsed with THF (1 L), andthe filtrate was concentrated to dryness to give the title compound (156g, 87%) as a pale yellow waxy solid: MS (ES) m/e 125.1 (M+H)³⁰ ; ¹H NMR(400 MHz, DMSO-d₆) δ 7.84 (dd, 1 H), 7.37 (m, 1 H), 6.53 (dd, 1 H), 5.65(br s,2 H), 5.16 (t, 1 H), 4.34 (d, J=4.6 Hz, 2 H).

b) 2-Amino-5-bromo-3-(hydroxymethyl)pyridine Hydrobromide

To a stirred solution of 2-amino-3-(hydroxymethyl)pyridine (156 g, 1.257mole) in HOAc (2.5 L) at ambient temperature was added bromine (64.1 mL,1.257 mole) dropwise over 1 hr. A suspension began to form during theaddition. An exotherm to 36° C. was controlled with an ice bath. Afterthe addition, the reaction mixture was stirred at ambient temperatureovernight. The yellow precipitate was filtered, washed with ether andair-dried to give the title compound (289 g, 81%): MS (ES) m/e 203.2(M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆, free base) δ 7.89 (d, J=2.3 Hz, 1 H),7.52 (s, 1 H), 5.92 (br s, 2 H), 5.29 (br s, 1 H), 4.30 (s, 2 H).

c) 2-Amino-5-bromo-3-(bromomethyl)pyridine Hydrobromide

A suspension of 2-amino-5-bromo-3-(hydroxymethyl)pyridine hydrobromide(289 g, 1.02 mole) in 48% aqueous HBr (2.9 L) was heated at reflux for12 hrs. Complete solution occurred during heating. The reaction mixturewas cooled and a crystalline precipitate formed. This was filtered andwashed with ethyl acetate and air dried to give the title compound (305g, 86%).

d) Methyl(±)-6-bromo-2-oxo-1,2,3,4-tetrahydro-1H-1,8-naphthyridine-3-carboxylate

To a solution of dimethyl malonate (224 g, 1.7 mole) in DMF (2 L) andTHF (2 L) stirred under argon and chilled to 3° C. with an ice-acetonebath was added NaH (60% Nujol dispersion, 69.2 g, 1.7 mole) in portionsover 1.5 hr. The anion solution was stirred for 15 min at ca. 5° C.,then 2-amino-5-bromo-3-(bromomethyl)pyridine hydrobromide (200 g, 0.56mole) was added in portions over 15 min. The reaction mixture wasallowed to warm to ambient temperature during overnight stirring andthen was heated to 80° C. for 2 hr. The reaction was then cooled andfiltered and the precipitate was washed with ethyl acetate. This solidwas then vigorously stirred in 2 L water for 15 min and again filteredand air-dried to give the title compound (113 g, 71%): MS (ES) m/e 286(M+H)⁺.

e) 6-Bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a suspension of methyl(±)-6-bromo-2-oxo-1,2,3,4-tetrahydro-1H-1,8-naphthyridine-3-carboxylate(170 g, 0.596 mole) in CH₃OH (10 L) was added 1.0 M NaOH (2.5 L). Thereaction mixture was stirred and heated at reflux for 5 hrs and thencooled to ambient temperature. The suspension was acidified with 1.0 MHCl (3.0 L) and then was stirred and heated at reflux overnight. Thereaction slurry was cooled and filtered and the solid was washed withwater and vacuum dried to give the title compound (122 g of the hydrate,90%) as an off-white solid, HPLC purity, 94%: MS (ES) m/e 228 (M+H)⁺.

Preparation 5 Preparation of6-bromo-3-methyl-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

a) 2-Amino-5-bromo-3-(methylaminomethyl)pyridine

A solution of 2-amino-5-bromo-3-(hydroxymethyl)pyridine (5.00 g, 24.6mmole), from Preparation 4 (b), in 48% aqueous HBr (50 mL) was heated atreflux for 12 hrs. The reaction was concentrated and toluene was used toazeotrope the residual H₂O. The resulting light brown solid was placedunder high vacuum overnight and used directly.

A solution of the 2-amino-3-(bromomethyl)-5-bromopyridine hydrobromidesalt (prepared above) in 40% aqueous methylamine (50 mL) and THF (50 mL)was stirred at RT overnight in a pressure bottle. The reaction solutionwas concentrated and extracted with EtOAc (2×100 mL). The combinedorganic phases were washed with H₂O, dried over Na₂SO₄ and concentrated.Purification on silica gel afforded the title compound (4.25 g, 80%) asa yellow oil: MS (ES) m/e 217 (M+H)⁺.

b) 6-Bromo-3-methyl-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

To a solution of 2-amino-5-bromo-3-(methylaminomethyl)pyridine (2.0 g,9.3 mmole) in dichloroethane (50 mL) was added 1,1′-carbonyldiimidazole(1.9 g, 11.5 mmole). The reaction was heated at 50° C. overnight andconcentrated. The residue was purified on silica gel (9:1 CHCl₃/CH₃OHcontaining 5% NH₄OH) to give the title compound (1.72 g, 77%) as anoff-white solid: MS (ES) m/e 243 (M+H)⁺.

Preparation 6 Preparation of(E)-3-(3H-imidazo[4.5-b]pyridin-6-yl)acrylic acid

a) 5-Bromo-2,3-diaminopyridine

To a suspension of 2-amino-5-bromo-3-nitropyridine (2.0 g, 9.17 mmole)in absolute EtOH (50 mL) was added SnCl₂ hydrate (9.3 g, 41.3 mmole),then the mixture was heated to reflux. After 3 hr the mixture was cooledto RT and concentrated. The residue was taken up in 2.0 M NaOH andextracted with EtOAc (3×). The combined organic layers were dried(MgSO₄), filtered, and concentrated to give the title compound (1.69 g,98%) which was sufficiently pure for use in the next step: MS (ES) m/e188/190 (M+H)⁺.

b) 6-Bromo-3H-imidazo[4,5-b]pyridine

5-Bromo-2,3-diaminopyridine (1.69 g, 8.99 mmole) was taken up in 96%formic acid (50 ML) and heated to reflux. After 18 hr the mixture wascooled to RT and concentrated. The residue was taken up in H₂O and thepH was adjusted to 7 with 2.0 M NaOH. The title compound (1.54 g, 87%)was collected as a solid by filtration, washed with H₂O, and dried invacuo: MS (ES) m/e 198/200 (M+H)⁺.

c) 6-Bromo-4-trityl-3H-imidazo[4,5-b]pyridine

To a suspension of 6-bromo-3H-imidazo[4,5-b]pyridine (1.2 g, 6.06 mmole)in CH₂Cl₂ (30 mL) was added Et₃N (1.3 mL, 9.09 mmole) then tritylchloride (2.03 g, 7.27 mmole) at RT. After 72 hr the mixture was washedwith H₂O (2×) and brine, then was dried (MgSO₄), filtered, andconcentrated under reduced pressure to afford the title compound. Thiswas used directly in the next step.

d) Benzyl (E)-3-(4-trityl-3H-imidazo[4,5-b]pyridin-6-yl)acrylate

A solution of 6-bromo-4-trityl-3H-imidazo[4,5-b]pyridine (from step a)(6.06 mmole), benzyl acrylate (1.18 g, 7.27 mmole), Pd(OAc)₂ (67 mg,0.30 mmole), P(o-tolyl)₃ (183 mg, 0.6 mmole), and (i-Pr)₂NEt (2.64 mL,15.15 mmole) in propionitrile (30 mL) was degassed (3×N₂/vacuum) thenheated to reflux. After 4 hr the mixture was cooled to RT andconcentrated. Flash chromatography on silica gel (30% EtOAc/hexanes)gave the title compound (1.75 g, 55% over 2 steps) as an off-white foam:¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=2.0 Hz, 1 H), 8.19 (d, J=2.0 Hz, 1H), 8.06 (s, 1 H), 7.77 (d, J=16.0 Hz, 1 H), 7.42–7.11 (m, 20 H), 6.48(d, J=16.0 Hz, 1 H), 5.25 (s, 2 H).

d) (E)-3-(3H-Imidazo[4,5-b]pyridin-6-yl)acrylic acid

Benzyl (E)-3-(4-trityl-3H-imidazo[4,5-b]pyridin-6-yl)acrylate (1.75 g,3.35 mmole) was dissolved in 4 N HCl in dioxane (20 mL). After 1 hr themixture was concentrated. The residue was taken up in 1:1 MeOH/H₂O (15mL). 2.0 N NaOH (15 mL, 15 mmole) was added and the mixture was heatedto reflux. After 18 hr the mixture was cooled to RT and concentrated toapproximately ⅓ volume. The mixture was adjusted to pH 4 using 10% HCl.The solid was collected by filtration, washed with H₂O, and dried invacuo to give the title compound (329 mg, 52% over 2 steps) as a whitesolid: ¹H NMR (400 MHz, d⁶-DMSO) δ 9.10 (s, 1 H), 8.94 (s, 1 H), 8.84(s, 1 H), 8.20 (d, J=16.0 Hz, 1 H), 7.10 (d, J=16.0 Hz, 1 H).

Preparation 7 Preparation of(E)-3-(3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-7-yl)acrylic acid

a) 3,4-Dihydro-2H-pyrido[3,2-b]-1,4-oxazine

To a suspension of 2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (2.0 g, 13.3mmole) in dry THF (40 mL) was added a solution of LiAlH₄ in THF (1.0 M,26.6 mL, 26.6 mmole) slowly at 0° C. After 1 hr the mixture was quenchedwith 2.0 M NaOH until a solid formed. The mixture was dried (MgSO₄),filtered, and concentrated under reduced pressure to give the titlecompound (1.44 g, 79%) as a white solid which was sufficiently pure foruse in the next step: MS (ES) m/e 137 (M+H)⁺.

b) 4-(tert-Butoxycarbonyl)-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine

To a solution of 3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine (1.44 g, 10.6mmole) and di-tert-butyl dicarbonate (2.78 g, 12.7 mmole) in dry THF (50mL) was added a solution of LiHMDS in THF (1.0 M, 12.7 mL, 12.7 mmole)dropwise at 0° C. After 30 min the mixture was quenched with saturatedNH₄Cl and extracted with EtOAc (3×). The combined organic layers weredried (MgSO₄), filtered, and concentrated. Flash chromatography onsilica gel (40% EtOAc/hexanes) gave the title compound (2.0 g, 80%) as aclear oil: MS (ES) m/e 237 (M+H)⁺.

c)4-(tert-Butoxycarbonyl)-7-bromo-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine

To a solution of4-(tert-butoxycarbonyl)-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine (2.0 g,8.46 mmole) in MeOH (40 mL) was added Br₂ (0.53 mL, 10.2 mmole) dropwiseat 0° C. After 1 hr the mixture was concentrated. The residue was takenup in 1:1 Et₂O/hexanes and filtered. The filtrate was concentrated underreduced pressure to give the title compound (1.27 g, 48%) as an oilwhich solidified under vacuum: ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1 H),7.33 (s, 1 H), 4.25 (m, 2 H), 3.92 (m, 2 H), 1.54 (s, 9 H).

d)(E)-3-[4-(tert-Butoxycarbonyl)-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-7-yl]acrylicacid

A solution of4-(tert-butoxycarbonyl)-7-bromo-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine(1.27 g, 4.03 mmole), benzyl acrylate (785 mg, 4.84 mmole), Pd(OAc)₂ (45mg, 0.20 mmole), P(o-tolyl)3 (122 mg, 0.4 mmole), and (i-Pr)₂NEt (1.76mL, 10.1 mmole) in propionitrile (20 mL) was degassed (3×N₂/vacuum) thenheated to reflux. After 18 hr the mixture was cooled to RT andconcentrated. Flash chromatography on silica gel (25% EtOAc/hexanes)gave the title compound (1.17 g, 73%) as a yellow oil: MS (ES) m/e 397(M+H)⁺.

e) (E)-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid

(E)-3-[4-(tert-Butoxycarbonyl)-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-7-yl]acrylicacid (1.17 g, 2.95 mmole) was dissolved in 4 N HCl in dioxane (15 mL).After 72 hr the mixture was concentrated. The residue was taken up in1:1 MeOH/H₂O (20 mL). 1.0 N LiOH (15 mL, 15 mmole) was added and themixture was heated to reflux. After 18 hr the mixture was cooled to RTand concentrated to approximately ⅓ volume. The mixture was adjusted topH 6 using 10% HCl. The solid was collected by filtration, washed withH₂O and dried in vacuo to give the title compound (315 mg, 52% over 2steps): MS (ES) m/e 207 (M+H)⁺.

Preparation 8 Preparation of 5-bromo-2,2′-dipyridylamine

To a stirred solution of 2,5-dibromopyridine (2.4 g, 10.1 mmole) in drytoluene (75 mL) were added 2-aminopyridine (1.0 g, 10.6 mmole),tris(dibenzylideneacetone)dipalladium(0) (183 mg, 0.2 mmole),1,3-bis(diphenylphosphino)propane (165 mg, 0.4 mmole) and sodiumtert-butoxide (1.35 g, 14 mmole). The reaction was purged with Ar thenheated with stirring at 70° C. After 4 h the reaction was cooled to RT,taken up in Et₂O (200 mL), washed with brine, dried (MgSO₄) andconcentrated to dryness. The remaining residue was purified by flashchromatography on silica gel (0.5% (5% NH₄OH/MeOH)/CHCl₃), trituratedwith hexane and dried under vacuum to give the title product (1.31 g,52%) as a pale yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 9.88 (s, 1 H),8.31 (s, 1 H), 8.23 (d, J=4.8 Hz, 1 H), 7.83 (m, 2 H), 7.67 (t, 1 H),7.62 (d, J=8.4 Hz, 1 H), 6.90 (t, 1 H); MS (ES) m/e 250.0 (M+H)⁺.

Preparation 9 Preparation of 1-methyl-2-(methylaminomethyl)-1H-indole

a) Ethyl 1-methyl-1H-indole-2-carboxylate

NaH (60% dispersion in mineral oil, 8.02 g, 200.49 mmole) was washedwith hexanes, then was suspended in dry DMF (530 mL). Solid ethylindole-2-carboxylate (25.29 g, 133.66 mmole) was added portionwise over5–10 min, allowing gas evolution to subside between additions. When theaddition was complete, the yellow mixture was stirred for 15 min, thenmethyl iodide (42 mL, 668.3 mmole) was added all at once. The reactionwas exothermic, and the internal temperature rose to 40–45° C. After 1hr, the reaction was quenched with 10% NH₄Cl (100 mL) and concentratedon the rotavap (high vacuum). The residue was partitioned betweenEt₂O(500 mL) and H₂O (100 mL), and the layers were separated. The Et₂Olayer was washed with H₂O (100 mL), dried (MgSO₄), and concentrated toleave the title compound (27.10 g, quantitative) as a light yellowsolid. This was used without further purification: TLC (10%EtOAc/hexanes) Rf=0.39.

b) N,1-Dimethyl-1H-indole-2-carboxamide

A suspension of ethyl 1-methyl-1H-indole-2-carboxylate (27.10 g, 133.34mmole) in 40% aqueous CH₃NH₂ (300 mL) and MeOH (30 mL) was stirred atRT. A solid tended to gradually creep up the walls of the flask, and waswashed down periodically with MeOH. The flask was tightly stoppered tokeep the material inside the flask. As the reaction proceeded, the soliddissolved, but eventually the product began to precipitate. The reactionwas stirred at RT for 5 days, then was concentrated to removeapproximately 200 mL of the solvent. The remaining residue was dilutedwith H₂O (300 mL), and the solid was collected by suction filtration andwashed with H₂O. Drying at 50–60° C. in high vacuum left the titlecompound (23.45 g, 93%) as a faintly yellow solid: ¹H NMR (300 MHz,CDCl₃) δ 7.63 (d, J=8.0 Hz, 1 H), 7.27 –7.43 (m, 2 H), 7.10 –7.20 (m, 1H), 6.80 (s, 1 H), 6.10–6.30 (m, 1 H), 4.06 (s, 3 H), 3.01 (d, J=4.9 Hz,3 H).

c) 1-Methyl-2-(methylaminomethyl)-1H-indole

A 3-liter 3-necked roundbottom flask equipped with overhead stirring wascharged with N,1-dimethyl-1H-indole-2-carboxamide (23.45 g, 124.58mmole) and anhydrous THF (170 mL). The solution was stirred while asolution of LiAlH₄ in THF (1.0 M, 250 mL, 250 mmole) was added viasyringe. Gas was evolved during the addition of the first 50 mL ofLiAlH₄ solution. When the addition was complete, the resulting lightyellow solution was heated at gentle reflux. After 23 hr, the reactionwas cooled in ice and quenched by the sequential dropwise addition ofH₂O (9.5 mL), 15% NaOH (9.5 mL), and H₂O (28.5 mL). The mixture wasstirred for 15 min, then was filtered through celite®, and the filterpad was washed thoroughly with THF. The filtrate was concentrated andthe residue was flash chromatographed on silica gel (10% MeOH/CHCl₃containing 0.5% conc. NH₄OH). The title compound (20.17 g, 93%) wasobtained as a light yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 7.56 (d, J=7.8Hz, 1 H), 7.02 –7.35 (m, 3 H), 6.38 (s, 1 H), 3.88 (s, 2 H), 3.75 (s,3H),2.49(s,3H).

Preparation 10 Preparation of 1-methyl-3-(methylaminomethyl)-1H-indole(Method A)

a) Methyl 1-methyl-1H-indole-3-carboxylate

NaH (60% dispersion in mineral oil, 8.56 g, 214.0 mmole) was addedportionwise, allowing for gas evolution, to a solution of methyl1H-indole-3-carboxylate (25.00 g, 142.7 mmole) in DMF (350 mL) at 0° C.When the NaH addition was complete, methyl iodide (44.4 mL, 713.5 mmole)was added at 0° C. The reaction was stirred at 0° C. for 15 minutes thenat RT overnight. The reaction was diluted with water and extracted withethyl acetate. The combined extracts were dried over K₂CO₃ andconcentrated to afford the title compound (26.00 g, 96%) as an orangesolid: MS (ES) m/e 190 (M+H)⁺.

b) N,1-Dimethyl-1H-indole-3-carboxamide

A suspension of methyl 1-methyl-1H-indole-3-carboxylate (4.30 g, 22.74mmole) in 40% aqueous CH₃NH₂ (400 mL) was stirred at RT. The flask wastightly stoppered to keep the material inside the flask. As the reactionproceeded the product began to precipitate. The reaction was stirred atRT for 3 days, then was concentrated to remove approximately 200 mL ofthe solvent. The remaining residue was diluted with H₂O (500 mL), andthe solid was collected by suction filtration and washed with H₂O. Flashchromatography on silica gel (ethyl acetate) gave the title compound(2.4 g, 56%) as a white solid: MS (ES) m/e 189 (M+H)⁺.

c) 1-Methyl-3-(methylaminomethyl)-1H-indole

A solution of LiAlH₄ in THF (1.0 M, 5.20 mL, 5.2 mmole) was slowly addedvia syringe to a solution of N,1-dimethyl-1H-indole-3-carboxamide (0.50g, 2.6 mmole) in anhydrous THF (15 mL). Gas was evolved during theaddition of the first 2 mL of LiAlH₄ solution. When the addition wascomplete, the resulting light yellow solution was heated at gentlereflux. After 23 hr, the reaction was cooled in ice and quenched by thesequential dropwise addition of H₂O (0.5 mL), 1.0 N NaOH (0.5 mL), andH₂O (0.5 mL). The mixture was stirred for 15 min, then was filteredthrough celite®, and the filter pad was washed thoroughly with THF. Thefiltrate was concentrated and the residue was flash chromatographed onsilica gel (10% MeOH/CHCl₃ containing 0.5% conc. NH₄OH) to afford thetitle compound (0.30 g, 67%) as a light yellow oil: MS (ES) m/e 175(M+H)⁺.

Preparation 11 Preparation of 1-methyl-3-(methylaminomethyl)-1H-indole(Method B)

To a solution of 1-methylindole-3-carboxaldehyde (10.0 g, 62.8 mmole) inMeOH (100 mL) was added a solution of 2.0 M CH₃NH₂ in MeOH (126 mL,252.0 mmole). The reaction was stirred at RT for 2 hrs, then wasconcentrated to a light yellow oil. This oil was dissolved in EtOH (300mL), and NaBH₄ (2.38 g, 62.8 mmole) was added. After 2 hrs the reactionwas concentrated to a slurry and dissolved in 1.0 N NaOH (75 mL). Theaqueous solution was extracted with Et₂O (2×200 mL) and the combinedorganic fractions were dried over Na₂SO₄ and concentrated. Flashchromatography on silica gel (9:1 CHCl₃/MeOH containing 5% NH₄OH) anddrying in high vacuum left the title compound (10.1 g, 92%) as a faintlyyellow oil: MS (ES) m/e 175 (M+H)⁺.

Preparation 12 Preparation of 2-methyl-3-(methylaminomethyl)indole

To a solution of 2-methylindole-3-carboxaldehyde (10.00 g, 62.84 mmole)in MeOH (100 mL) was added 2 M CH₃NH₂ in MeOH (200 mL). After stirringfor 3 hours at RT, the reaction solution was concentrated to a yellowoil which solidified under vacuum. This solid was dissolved in ethanol(350 mL) and NaBH4 (2.38 g, 62.8 mmole) was added. The reaction wasstirred at RT for 6 hours, then was concentrated under vacuum. Theremaining residue was diluted with saturated aqueous Na₂CO₃ (50 mL) andextracted with EtOAc (2×200 mL). The organic phase was separated, washedwith brine, and dried over Na₂SO₄. Flash chromatography on silica gel(9:1 CHCl₃/MeOH containing 5% NH₄OH) and drying under high vacuum gavethe title compound (6.88 g, 63%) as a faintly yellow viscous solid: MS(ES) m/e 175 (M+H)⁺.

Preparation 13 Preparation of1,3-dimethyl-2-(methylaminomethyl)-1H-indole

a) 1,3-Dimethyl-1H-indole

To a stirred solution of 3-methylindole (15.0 g, 114 mmole) in dry DMF(200 mL) was added NaH (60% dispersion in oil, 5.0 g, 125 mmole) inportions. Gas evolution was observed. The mixture was stirred for 30min, then iodomethane (8 mL, 129 mmole) was added in one portion. Thereaction became exothermic and was cooled in an ice bath. After 16 hr atRT, the reaction was concentrated under vacuum and the residue was takenup in ethyl acetate. The solution was washed with H₂O then with brine,dried (MgSO₄), and concentrated to dryness. Purification by short pathdistillation under vacuum (bp 88–92° C., 0.5 mmHg) gave the titlecompound (16.10 g, 97%) as a pale yellow oil: ¹H NMR (400 MHz, CDCl₃) δ7.47 (d, J=7:9 Hz, 1 H), 7.35 (d, J=8.2 Hz, 1 H), 7.13 (t, 1 H), 7.06(s, 1 H), 7.00 (t, 1 H), 3.71 (s, 3 H), 2.24 (s, 3 H).

b) 1,3-Dimethyl-1H-indole-2-carboxaldehyde

To a stirred solution of phosphorus oxychloride (7.0 mL, 75 mmole) inDMF (25 mL) was added dropwise a solution of 1,3-dimethylindole (12.0 g,83 mmole) in dry DMF (6.0 mL). The reaction was stirred at RT for 2 hrthen was poured onto ice. The mixture was basified with a solution ofNaOH (13.2 g, 330 mmole) in H₂O (44 mL), then was extracted with Et₂O(2×50 mL). The combined organic layers were washed with brine, dried(MgSO₄), and concentrated under vacuum. Flash chromatography on silicagel (10% ethyl acetate/hexanes) gave the title compound (13.03 g, 91%)as an off-white solid: LCMS (ES) m/e 174.2 (M+H)⁺; ¹H NMR (400 MHz,CDCl₃) δ 10.16 (s, 1 H), 7.68 (d, J=8.1 Hz, 1 H), 7.42 (t, 1 H), 7.32(d, J=8.5 Hz, 1 H), 7.15 (t, 1 H), 4.04 (s, 3 H), 2.63 (s, 3 H).

c) 1 ,3-Dimethyl-2-(methylaminomethyl)-1H-indole

To 1,3-dimethyl-1H-indole-2-carboxaldehyde (13.0 g, 75 mmole) was addeda solution of 2.0 M methylamine in methanol (150 mL, 300 mmole) and HOAc(4.3 mL, 75 mmole). The solution was stirred at RT for 4 hr, then wascooled to 0° C., and sodium cyanoborohydride (5.0 g, 80 mmole) was addedportionwise over 5 min. The reaction was then allowed to warm to RT.After 16 hr, the reaction was concentrated under vacuum and the residuewas taken up in Et₂O. The solution was washed with 1.0 N NaOH then withbrine, dried (Na₂SO₄), and concentrated to dryness. Flash chromatographyon silica gel (95:5 CHCl₃/methanol containing 5% NH₄OH) gave the titlecompound (7.34 g, 52%) as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.53(d, J=7.8 Hz, 1 H), 7.26 (d, J=7.8 Hz, 1 H), 7.20 (t, 1 H), 7.09 (t, 1H), 3.88 (s, 2 H), 3.76 (s, 3 H), 2.46 (s, 3 H), 2.32 (s, 3 H), 1.36 (brs, 1 H).

Preparation 14 Preparation of1-methyl-3-(methylaminomethyl)-1H-pyrrolo[2,3-b]pyridine

a) 1-Methyl-1H-pyrrolo[2,3-b]pyridine

According to the procedure of Preparation 13 (a), except substituting7-azaindole (2.28 g, 1.83 mmole) for the 3-methylindole, the titlecompound (1.4 g, 58%) was prepared as a yellow oil: MS (ES) m/e 133(M+H)⁺.

b) 1-Methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde

According to the procedure of Preparation 13 (b), except substituting1-methyl-1H-pyrrolo[2,3-b]pyridine (0.7 g, 5.3 mmole) for the1,3-dimethylindole, the title compound (0.4 g, 47%) was prepared as awhite solid: MS (ES) m/e 161 (M+H)⁺.

c) 1-Methyl-3-(methylaminomethyl)-1H-pyrrolo[2,3-b]pyridine

According to the procedure of Preparation 13 (c), except substituting1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.4 g, 2.5 mmole)for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.2g, 45%) was prepared as a yellow oil: MS (ES) m/e 176 (M+H)⁺.

Preparation 15 Preparation of2-methyl-3-(methylaminomethyl)benzo[b]thiophene

a) 2-Methylbenzo[b]thiophene-3-carboxaldehyde

SnCl₄ (20 mL, 67 mmole) was added over 5 min to a stirred solution of2-methylbenzo[b]thiophene (5.0 g, 33.7 mmole) in CH₂Cl₂ (75 mL) at 0° C.under argon. After 15 minutes, dichloromethyl methyl ether (3.7 mL, 41mmole) was added. The reaction became a yellowish colored suspension.The reaction was allowed to warm to RT and stirred for 16 h, then waspoured onto ice water (200 mL). The aqueous mixture was acidified with1.0 N HCl (100 mL) and stirred until the suspension dissolved. Theorganic phase was separated, dried (MgSO₄), and concentrated undervacuum. Purification by flash chromatography on silica gel (10% ethylacetate/hexane) gave the title compound (5.83 g, 98%) as a whitecrystalline solid: ¹H NMR (400 MHz, CDCl₃) δ 10.38 (s, 1 H), 8.61 (d,J=8.1 Hz, 1 H), 7.77 (d, J=8.0Hz, 1 H), 7.48 (t, 1 H), 7.39 (t, 1 H),2.93 (s, 3 H).

b) 2-Methyl-3-(methylaminomethyl)benzo[b]thiophene

According to the procedures of Preparation 1, except substituting2-methylbenzo[b]thiophene-3-carboxaldehyde (5.0 g, 28.4 mmole) for1-methylindole-3-carboxaldehyde, the title compound (4.89 g, 90%) wasprepared as an oil which solidified in the freezer: ¹H NMR (400 MHz,CDCl₃) δ 7.78 (d, J=7.9 Hz, 1 H), 7.75 (d, J=7.9 Hz, 1 H), 7.37 (t, 1H), 7.29 (t, 1 H), 3.95 (s, 2 H), 2.60 (s, 3 H), 2.50 (s, 3 H).

Preparation 16 Preparation of 3-(methylaminomethyl)-1H-indole

a) 3-(Methylaminomethyl)-1H-indole

To a solution of indole-3-carboxaldehyde (5.4 g, 34.1 mmole) in MeOH (30mL) was added a solution of 2.0 M CH₃NH₂ in MeOH (51.3 mL, 102.6 mmole).The reaction was stirred at RT overnight, then was concentrated to alight yellow oil. This oil was dissolved in EtOH (40 mL), and NaBH₄ (1.3g, 34.1 mmole) was added. After 16 hrs the reaction was concentrated toa slurry and dissolved in 10% Na₂CO₃(100 mL). The aqueous solution wasextracted with EtOAc (2×200 mL) and the combined organic fractions weredried over Na₂SO₄ and concentrated. Drying in high vacuum left the titlecompound (5.2 g, 94%) as a faintly yellow oil: MS (ES) m/e 161 (M+H)⁺.

Preparation 17 Preparation of 1-benzyl-3-(methylaminomethyl)-1H-indole

a) 3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole

N-(Benzyloxycarbonyloxy)succinimide (8.9 g, 35.7 mmole) was added to asolution of 3-(methylaminomethyl)-1H-indole (5.2 g, 32.5 mmole), fromPreparation 16, and triethylamine (5.0 mL, 65.7 mmole) in DMF (100 mL)at RT. The reaction was stirred overnight then was concentrated invacuo. The residue was diluted with water and the mixture was extractedwith ethyl acetate. The combined extracts were dried over Na₂SO₄ andconcentrated. Flash chromatography on silica gel (33% ethylacetate/hexanes) gave the title compound (7.0 g, 74%) as an off-whitesolid: MS (ES) m/e 295 (M+H)⁺.

b) 3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1-benzyl-1H-indole

NaH (60% dispersion in mineral oil, 0.15 g, 3.8 mmole) was addedportionwise, allowing for gas evolution, to a solution of3-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole (0.7 g, 2.5mmole) in DMF (25 mL) at 0° C. When the NaH addition was complete,benzyl bromide (1.2 mL, 10.0 mmole) was added at 0° C. The reaction wasstirred at 0° C. for 15 minutes then at RT overnight. The reaction wasdiluted with water and extracted with ethyl acetate. The combinedextracts were dried over Na₂SO₄ and concentrated. Flash chromatographyon silica gel (33% ethyl acetate/hexanes) gave the title compound (0.9g, 93%) as an off white solid: MS (ES) m/e 385 (M+H)⁺.

c) 1-Benzyl-3-(methylaminomethyl)-1H-indole

3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1-benzyl-1H-indole (0.9 g,2.3 mmole) was added to a suspension of Pearlman's catalyst (about 0.30g) in MeOH at RT in a Parr flask. The reaction was placed under 50p.s.i. of H₂ and shaken for 5 hr. The mixture was filtered throughcelite® and the filter pad was washed with MeOH. The filtrate wasconcentrated to afford the title compound (0.5 g, 86%) as a light yellowsolid: MS (ES) m/e 251 (M+H)⁺.

Preparation 18 Preparation of2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene

a) 2,3-Dihydro-1H-3a-azacyclopenta[a]indene-8-carboxaldehyde

According to the procedure of Preparation 13 (b), except substituting2,3-dihydro-1H-3a-azacyclopenta[a]indene (J. Med. Chem. 1965, 8, 700;0.24 g, 1.53 mmole) for the 1,3-dimethylindole, the title compound (0.17g, 60%) was prepared as a yellow solid: MS (ES) m/e 186 (M+H)⁺.

b) 2,3-Dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]Indene

According to the procedure of Preparation 13 (c), except substituting2,3-dihydro-1H-3a-azacyclopenta[a]indene-8-carboxaldehyde (0.17 g, 0.92mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the titlecompound (0.1 g, 54%) was prepared as a yellow oil: MS (ES) m/e 201(M+H)⁺.

Preparation 19 Preparation of1,4-dimethyl-3-(methylaminomethyl)-1H-indole

a) 1,4-Dimethyl-1H-indole

According to the procedure of Preparation 9 (a), except substituting4-methylindole for ethyl indole-2-carboxylate, the title compound (1.5g, 94%) was prepared as an amber oil: MS (ES) m/e 146.2 (M+H)⁺.

b) 1,4-Dimethyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 9 (b), except substituting1,4-dimethyl-1H-indole for 1,3-dimethylindole, the title compound (1.8g, 95%) was prepared as an amber oil: MS (ES) m/e 174.2 (M+H)⁺.

c) 1,4-Dimethyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 11, except substituting1,4-dimethyl-1H-indole-3-carboxaldehyde for1,3-dimethyl-1H-indole-1-carboxaldehyde, the title compound (1.9 g, 99%)was prepared as an oil: MS (ES) m/e 189.0 (M+H)⁺.

Preparation 20 Preparation of(E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt

a) 3,3,5-Tribromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one

To a solution of 7-azaindole (5.0 g, 42.3 mmole) in H₂O (210 mL) andtert-butanol (210 mL) at RT was added Br₂ (27 mL, 529.0 mmole) over 20minutes. The reaction was stirred for 12 hr at RT and concentrated to anaqueous slurry. The reaction contents were made basic with solid NaHCO₃and the remaining solid was filtered and washed with H₂O. The filteredmass was dried under high vacuum to give the title compound (14.0 g,89%) as a brown solid: MS (ES) m/e 370 (M+H)⁺.

b) 5-Bromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one

To a stirred solution of3,3,5-tribromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (2.0 g, 5.4 mmole)in acetic acid (50 mL) at RT was added Zn metal. The reaction becameexothermic and was cooled by the use of an ice bath during the initial30 minutes. After 5 hr the reaction was filtered through celite®, andthe filter pad was washed with EtOAc. The filtrate was concentratedunder vacuum and neutralized with saturated aqueous NaHCO₃ solution. Theneutralized aqueous filtrate was then extracted with EtOAc (2×200 mL),and the combined organic extracts were dried over Na₂SO₄ andconcentrated to a solid. The solid was washed with hexanes and driedunder high vacuum to give the title compound (0.36 g, 32%): MS (ES) m/e215 (M+H)⁺. This was used without further purification.

c) tert-Butyl (E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylate

A solution of 5-bromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (2.0 g,9.49 mmole), tert-butyl acrylate (1.8 g, 14.1 mmole), Pd(OAc)₂ (0.32 g,1.4 mmole), tri-ortho-tolylphosphine (0.57 g, 1.9 mmole), anddiisopropylethylamine (4.9 mL, 28.2 mmole) in propionitrile (100 mL) andDMF (10 mL) was heated at reflux overnight. The dark mixture wasfiltered through celite®, and the filtrate was concentrated. Flashchromatography on silica (9:1 CHCl₃/CH₃OH containing 5% NH₄OH) gave thetitle compound (0.80 g, 33%) as a light yellow solid. MS (ES) m/e261(M+H)⁺.

d) (E)-3-(2-Oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloridesalt

To a stirred solution of tert-butyl(E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylate (0.80 g, 3.1 mmole) inCH₂Cl₂(50 mL) at RT was added trifluoroacetic acid (20 mL). After 1 hrthe reaction solution was concentrated and the residue was dried undervacuum. An HCl solution (20 mL, 4 M in dioxane) was added and themixture was concentrated under vacuum. The remaining solid wastriturated with diethyl ether and filtered giving the title compound(0.74 g, 33%) as a white solid: MS (ES) m/e 205 (M+H−HCl)⁺.

Preparation 21 Preparation of 1-ethyl-3-(methylaminomethyl)-1H-indole a)3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl-1-ethyl-1H-indole

According to the procedure of Preparation 17 (b), except substitutingethyl iodide (0.92 mL, 11.44 mmole) for the benzyl bromide, the titlecompound (0.90 g, 98%) was prepared as a white solid: MS (ES) m/e 323(M+H)⁺.

b) 1-Ethyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 17 (c), except substituting3-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1-ethyl-1H-indole (0.90 g,2.80 mmole) for the3-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1-benzyl-1H-indole, thetitle compound (0.50 g, 94%) was prepared as a white solid: MS (ES) m/e189 (M+H)⁺.

Preparation 22 Preparation of1-isopropyl-3-(methylaminomethyl)-1H-indole

a) 3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1-isopropyl-1H-indole

According to the procedure of Preparation 17 (b), except substitutingisopropyl iodide (1.34 mL, 11.84 mmole) for the benzyl bromide, thetitle compound (0.99 g, 99%) was prepared as a white solid: MS (ES) m/e337 (M+H)⁺.

b) 1-ethyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 17 (c), except substituting3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1-isopropyl-1H-indole(0.99 g, 2.98 mmole) for the3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl)-1-benzyl-1H-indole, thetitle compound (0.49 g, 82%) was prepared as a white solid: MS (ES) m/e405 (2M+H)⁺.

Preparation 23 Preparation of 1-acetyl-3-(methylaminomethyl)-1H-indole

a) 1-Acetyl-3-(methylaminomethyl)indole

According to the procedure of Preparation 16 (a), except substitutingN-acetyl-3-indole carboxaldehyde (1.33 g, 7.10 mmole), the titlecompound (1.40 g, 99%) was prepared as a light yellow oil: MS (ES) m/e203 (M+H)⁺.

Preparation 24 Preparation of N-91H-indol-3-ylmethyl)-N-methylacrylamide

a) N-(1H-indol-3-ylmethyl)-N-methylacrylamide

Acryloyl chloride (0.33 mL, 4.10 mmole) was added to a solution of3-(methylaminomethyl)-1H-indole (0.60 g, 3.70 mmole) and Et₃N (1.03 mL,7.40 mmole) in CH₂Cl₂ (30 mL) at 0° C. The reaction was held at 0° C.for ten minutes, then was stirred overnight at RT. The solution wasconcentrated in vacuo and the residue was diluted with water. Thesolution was extracted with ethyl acetate, and the combined organicextracts were washed with brine and dried over Na₂SO₄. The titlecompound (0.64 g, 80%) was obtained as a light yellow solid: MS (ES) m/e215 (M+H)⁺.

Preparation 25 Preparation ofN-(1-benzyl-1H-indol-3-ylmethyl)-N-methylacrylamide

a) N-(1-Benzyl-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Preparation 24 (a), except substituting1-benzyl-3-(methylaminomethyl)-1H-indole (1.30 g, 5.20 mmole) for of3-(methylaminomethyl)-1H-indole, the title compound (1.40 g, 89%) was abrown solid: MS (ES) m/e 305 (M+H)⁺.

Preparation 26 Preparation ofN-[1-(2-dimethylamino)-1H-indol-3-ylmethyl]-N-methylacrylamide

a) N-[1-(2-dimethylamino)-1H-indol-3-ylmethyl]-N-methylacrylamide

According to the procedure of Preparation 25 (a), except substituting[1-(2-dimethylamino)]-3-(methylaminomethyl)-1H-indole (1.00 g, 2.74mmole) for of 3-(methylaminomethyl)-1H-indole, the title compound (0.50g, 79%) was a yellow solid: MS (ES) m/e 463 (2M+H)⁺.

Preparation 27 Preparation of3-bromo-5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one

a) 8-Benzylidene-5,6,7,8-tetrahydro-quinoline

Benzaldehyde (3.59 mL, 35.30 mmole) was added to a solution of5,6,7,8-tetrahydro-quinoline (4.70 g, 35.30 mmole) in acetic anhydride(25 mL), and the solution was heated to reflux under a nitrogenatmosphere. After overnight at reflux, the reaction was concentrated invacuo. The residue was diluted with water and extracted with ethylacetate. The combined organic extracts were washed with brine, driedover Na₂SO₄, and concentrated. The residue was purified by flashchromatography on silica gel (33% EtOAc/hexanes) to give the titlecompound (4.50 g, 58%) as a waxy yellow solid after drying in vacuo: MS(ES) m/e 222 (M+H)⁺.

b) 6,7-Dihydro-5H-quinolin-8-one

A solution of 8-benzylidene-5,6,7,8-tetrahydro-quinoline (4.30 g, 19.4mmole) in CH₂Cl₂ (150 mL) was reacted with ozone at −78° C. for 30minutes. Dimethyl sulfide (5 mL) was added, and the reaction was warmedto RT and stirred overnight. The mixture was concentrated in vacuo andthe residue was purified by flash chromatography on silica gel (EtOAc).The title compound (2.20 g, 79%) was obtained as an off-white solidafter drying in vacuo: MS (ES) m/e 148 (M+H)⁺.

c) 6,7-Dihydro-5H-quinolin-8-one Oxime

According to the reported procedure (J. Het. Chem. 1978, 15, 249–251),6,7-dihydro-5H-quinolin-8-one was reacted with hydroxylaminehydrochloride to afford the title compound (2.40 g, 96%) as a whitesolid after drying in vacuo: MS (ES) m/e 163 (M+H)⁺.

d) 6,7-Dihydro-5H-quinolin-8-one, O-toluenesulfonyloxime

According to the reported procedure (J. Het. Chem. 1978, 15, 249–251),6,7-dihydro-5H-quinolin-8-one oxime was reacted with p-toluenesulfonylchloride to afford the title compound (4.00 g, 85%) as a white solidafter drying in vacuo: MS (ES) m/e 317 (M+H)⁺.

e) 5,6,7,9-Tetrahydro-pyrido[2,3-b]azepin-8-one

According to the reported procedure (J. Het. Chem. 1978, 15, 249–251),6,7-dihydro-5H-quinolin-8-one, O-toluenesulfonyloxime was reacted toafford the title compound (1.00 g, 50%) as a white solid after drying invacuo: MS (ES) m/e 163 (M+H)⁺.

f) 3-Bromo-5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one

A 10% solution of bromine (0.57 mL, 11.1 mmole) in CH₂Cl₂ was addeddropwise over 1 hr to a solution of5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one (1.20 g, 7.4 mmole) inCH₂Cl₂ at RT. The mixture was stirred at RT overnight, then wasconcentrated in vacuo. The residue was diluted with 10% Na₂CO₃ andextracted with EtOAc. The combined organics were dried over Na₂SO₄ andconcentrated. Flash chromatography on silica gel (EtOAc) gave the titlecompound (1.00 g, 56%) as a light yellow solid after drying in vacuo: MS(ES) m/e 241/243.

Preparation 28 Preparation of5-bromo-2-(methylaminocarbonylmethyl)aminopyridine

a) 5-Bromo-2-(tert-butoxycarbonyl)aminopyridine

To a solution of 2-amino-5-bromopyridine (27.56 g, 159 mmole) in THF(150 mL) was added di-tert-butyl dicarbonate (38 g, 174 mmole). Thereaction was gradually heated to reflux. Vigorous gas evolution wasobserved initially, which subsided after approximately 10 min. After 18hr at reflux, the reaction was concentrated to dryness. The residue wastriturated with 1:1 Et₂O/petroleum ether, filtered and dried undervacuum to give the title compound (34.79 g, 80%) as a white solid: ¹HNMR (400 MHz, CDCl₃) δ 8.49 (s, 1 H), 8.37 (dd, 1 H), 7.94 (d, J=9.0 Hz,1 H), 7.77 (dd, 1 H), 1.57 (s, 9 H).

b)5-Bromo-2-[N-(tert-butoxycarbonyl)-N-(methoxycarbonylmethyl)amino)pyridine

To a solution of 5-bromo-2-(tert-butoxycarbonyl)aminopyridine (25.0 g,91.5 mmole) in DMF (400 mL) was added portionwise with stirring a 60%dispersion of NaH in mineral oil (4.0 g, 100 mmole). The reaction wasstirred for 15 min, then methyl bromoacetate (15 mL, 158.5 mmole) wasadded dropwise over 15 min. After stirring for 18 h at room temperaturethe reaction was concentrated to dryness. The remaining residue wastaken up in EtOAc (200 mL) and H₂O (200 mL) and filtered to removeinsoluble material. The EtOAc phase was separated, washed with brine,dried (Na₂SO₄) and concentrated to dryness. Purification by flashchromatography on silica gel (10% EtOAc/Hexane) gave the title compound(16.56 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1 H), 7.73 (d, J=2.5Hz, 1 H), 7.71 (d, J=2.5 Hz, 1 H), 4.69 (s, 2 H), 3.75 (s, 3 H), 1.51(s,9H).

c) 5-Bromo-2-(methoxycarbonylmethyl)aminopyridine

A 50% solution of TFA in CH₂Cl₂ (200 mL) was added to5-bromo-2-[N-(tert-butoxycarbonyl)-N-(methoxycarbonylmethyl)amino]pyridine(16.5 g, 46 mmole). After stirring for 45 min the reaction wasconcentrated to dryness, and the residue was diluted with 1.0 N Na₂CO₃(300 mL). The mixture was extracted with EtOAc (300 mL), and the organiclayer was washed with brine, dried (Na₂SO₄), and concentrated to drynessunder vacuum. The title compound (11.32 g, 100%) was obtained as a whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J=2.3 Hz, 1 H), 7.48 (dd, 1H), 6.40 (d, J=8.8 Hz, 1 H), 4.95 (br s, 1H), 4.12 (d, J=5.5 Hz, 2 H),3.78 (s, 3H).

d) 5-Bromo-2-(methylaminocarbonylmethyl)aminopyridine

A solution of 2.0 M methylamine in MeOH (75 mL) was added to5-bromo-2-(methoxycarbonylmethyl)aminopyridine (2.9 g, 12 mmole). Thereaction was stirred for 24 h then was concentrated to dryness. Theresidue was triturated with 10% petroleum ether/Et₂O (100 mL), then wascollected and dried under vacuum to give the title compound (2.96 g,100%) as an off-white solid: MS (ES) m/e 244.2 (M+H)⁺.

Preparation 29 Preparation of methyl 2-amino-5-bromonicotinate

a) Methyl 2-aminonicotinate

Concentrated H₂SO₄ (20 mL, 360 mmole) was added dropwise over 5 minutesto a suspension of 2-aminonicotinic acid (25 g, 181 mmole) in MeOH (400mL), and the mixture was heated at reflux; a homogeneous solution formedwithin 5 min. After 72 h, the reaction was cooled to room temperatureand concentrated under vacuum. The residue was basified with 1.0 NNa₂CO₃ (500 mL) (Gas evolution!) and extracted with EtOAc (500 mL). Theorganic layer was washed with brine, dried (Na₂SO₄), and concentrated todryness to give the title compound (19.6 g, 71%) as a white solid: ¹HNMR (400 MHz, CDCl₃) δ 8.22 (dd, 1 H), 8.13 (dd, 1 H), 6.63 (dd, 1 H),6.30 (br s, 2 H), 3.89 (s, 3 H).

b) Methyl 2-amino-5-bromonicotinate

Bromine (0.7 mL, 14 mmole) was added dropwise to a stirred solution ofmethyl 2-aminonicotinate (2.0 g, 13 mmole) in HOAc (50 mL). A suspensionformed within 30 min. The reaction was allowed to stir at roomtemperature for 2 h, then was concentrated under vacuum. The residue wastriturated with 1.0 N Na₂CO₃ (50 mL) and the solid was collected bysuction filtration. The solid was washed with H₂O (50 mL) and driedunder vacuum to give the title compound (2.95 g, 98%) as a pale yellowsolid: ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=2.5 Hz, 1 H), 8.23 (d, J=2.5Hz, 1 H), 6.40 (br s, 2 H), 3.90 (s,3 H).

Preparation 30 Preparation of(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]acrylic acidhydrochloride salt

a) tert-Butyl(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]acrylate

A solution of 5-bromo-2-(methoxycarbonylmethyl)aminopyridine (4.69 g,19.1 mmole, from Preparation 28 (c)), tert-butyl acrylate (11.2 mL, 76.5mmole), DIEA (6.7 mL, 38.5 mmole), Pd(OAc)₂ (215 mg, 1 mmole), andP(o-tol)₃ (583 mg, 2 mmole) in propionitrile (100 mL) was purged withAr, then was heated at reflux. After 18 h, the reaction was allowed tocool to room temperature then was concentrated to dryness. The residuewas purified by flash chromatography on silica gel (40% EtOAc/hexane) togive the title compound (5.21 g, 93%) as a white solid: ¹H NMR (400 MHz,CDCl₃) δ 8.19 (s, 1 H), 7.62 (dd, 1 H), 7.47 (d, J=16.0 Hz, 1 H), 6.48(d, J=8.7 Hz, 1 H), 6.17 (d, J=15.9 Hz, 1 H), 5.21 (br s, 1 H), 4.20 (d,J=5.4 Hz, 2 H), 3.79 (s, 3 H), 1.52 (s, 1 H).

b) (E)-3-[6-[N-(Methoxycarbonylmethyl)amino]pyridin-3-yl]acrylic acidhydrochloride salt

A solution of 50% TFA in CH₂Cl₂ (75 mL) was added to tert-butyl(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]acrylate (5.20 g,17.8 mmole). The reaction was stirred at room temperature for 45 minthen was concentrated under vacuum. The residue was taken up in 4.0 NHCl in dioxane (75 mL), stirred for 5 min, then concentrated to drynessunder vacuum. The remaining solid was triturated with 1:1 Et₂O/petroleumether, filtered and dried under vacuum to give the title compound (4.87g, 100%) as a white solid: MS (ES) m/e 237.2 (M+H)⁺.

Preparation 31 Preparation of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt

a) tert-Butyl(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate

A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (12.99 g, 57mmole), tert-butyl acrylate (34 mL, 232 mmole), DIEA (21.2 mL, 122mmole), Pd(OAc)₂ (1.3 g, 5.8 mmole) and P(o-tol)₃ (3.5 g, 11.5 mmole) inpropionitrile (200 mL) and DMF (50 mL) was purged with Ar, then washeated at reflux. After 18 h the reaction was allowed to cool to roomtemperature and was concentrated to dryness. The residue was purified byflash chromatography on silica gel (2–4% MeOH/CHCl₃). The resultingresidue was triturated with 1:1 Et₂O/petroleum ether, collected, anddried, and the resulting material was triturated with 1:1 MeOH/H₂O,collected, and dried, to give the title compound (7.09 g, 45%) as anoff-white solid: ¹H NMR (400 MHz, d₆-DMSO) δ 10.70 (s, 1 H), 8.35 (d,J=2.0 Hz, 1 H), 8.04 (s, 1 H), 7.50 (d, J=16.0 Hz, 1 H), 6.51 (d, J=16.0Hz, 1 H), 2.89 (t, 2 H), 2.53 (t, 2 H), 1.48 (s, 9H); MS (ES) m/e 275.2(M+H)⁺.

b) (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt

To tert-butyl(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate (7.0 g,25.5 mmole) was added 1:1 TFA/CH₂Cl₂ (100 mL). The reaction was stirredfor 30 min, then was concentrated under vacuum. The residue wassuspended in 4 N HCl/dioxane (100 mL), triturated, and concentrated todryness. The resulting solid was triturated with Et₂O, collected, anddried under vacuum to give the title compound (6.55 g, 100%) as aoff-white solid: ¹H NMR (400 MHz, d₆-DMSO) δ 10.72 (s, 1 H), 8.35 (d,J=2.0 Hz, 1 H), 8.04 (s, 1 H), 7.54 (d, J=16.0 Hz, 1 H), 6.51 (d, J=16.0Hz, 1 H), 2.91 (t, 2 H), 2.53 (t, 2 H); MS (ES) m/e 219.0 (M+H)⁺.

Preparation 32 Preparation ofN-methyl-N-(1-methyl-1H-pyrrol[2,3-b]pyridin-ylmethyl)acrylamide

A solution of acryloyl chloride (0.43 g, 5.58 mmole) in CH₂Cl₂ (10 mL)was added dropwise with stirring to a solution of1-methyl-3-(methylaminomethyl)-1H-pyrrolo[2,3-b]pyridine (0.93 g, 5.28mmole) and triethylamine (0.8 mL, 5.8 mmole) in CH₂Cl₂ (40 mL) at 0° C.under N₂. The reaction was allowed to warm to RT and stir for 1 hr, thenwas concentrated in vacuo. The residue was dissolved in 10% NaOH andextracted with CH₂Cl₂ (3×20 mL). The extracts were dried (MgSO₄),filtered, and concentrated. The residual oil was flash chromatographedon silica gel (5% MeOH/CH₂Cl₂) to give the title compound (1.0 g, 80%)as a colorless oil: MS (ES) m/e 216 (M+H)⁺.

Preparation 33 Preparation of7-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

a) 7-Fluoro-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 11 (b), except substituting7-fluoroindole (0.5 g, 3.7 mmole) for the 1,3 dimethylindole, the titlecompound (0.5 g, 83%) was prepared as a waxy solid: MS (ES) m/e 164(M+H)⁺.

b) 7-Fluoro-1-methyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 9 (a), except substituting7-fluoro-1H-indole-3-carboxaldehyde (0.5 g, 3.1 mmole) for the ethylindole-2-carboxylate, the title compound (0.23 g, 43%)was prepared as aviscous oil: MS (ES) m/e 178 (M+H)⁺.

c) 7-Fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 11 (c), except substituting7-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.23, 1.3 mmole) for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.18 g,72%) was prepared as a viscous oil: MS (ES) m/e 193 (M+H)⁺.

Preparation 34 Preparation of6-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

a) 6-Fluoro-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 11 (b), except substituting6-fluoroindole (0.5 g, 3.7 mmole) for the 1,3-dimethylindole, the titlecompound (0.3 g, 50%) was prepared as a waxy solid: MS (ES) m/e164(M+H)⁺.

b) 6-Fluoro-1-methyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 9 (a), except substituting6-fluoro-1H-indole-3-carboxaldehyde (0.3 g, 1.8 mmole) for the ethylindole-2-carboxylate, the title compound (0.3 g, 94%) was prepared as aviscous oil: MS (ES) m/e 178 (M+H)⁺.

c) 6-Fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 11 (c), except substituting6-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.3 g, 1.69 mmole) for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.11 g,35%) was prepared as a viscous oil: MS (ES) m/e 193 (M+H)⁺.

Preparation 35 Preparation of5-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

a) 5-Fluoro-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 11 (b), except substituting5-fluoroindole (0.5 g, 3.7 mmole) for the 1,3-dimethylindole, the titlecompound (0.3 g, 50%) was prepared as a waxy solid: MS (ES) m/e 164(M+H)⁺.

b) 5-Fluoro-1-methyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 9 (a), except substituting5-fluoro-1H-indole-3-carboxaldehyde (0.3 g, 1.8 mmole) for the ethylindole-2-carboxylate, the title compound (0.16 g, 50%) was prepared as aviscous oil: MS (ES) m/e 178 (M+H)⁺.

c) 5-Fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 11 (c), except substituting5-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.3 g, 1.69 mmole) for the1,3 dimethyl-1H-2-carboxaldehyde, the title compound (0.11 g, 35%) wasprepared as a viscous oil: MS (ES) m/e 193 (M+H)⁺.

Preparation 36 Preparation of4-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

a) 4-Fluoro-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 11 (b), except substituting4-fluoroindole (0.5 g, 3.7 mmole) for the 1,3-dimethylindole, the titlecompound (0.41 g, 68%) was prepared as a waxy solid: MS (ES) m/e164(M+H)⁺.

b) 4-Fluoro-1-methyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 9 (a), except substituting4-fluoro-1H-indole-3-carboxaldehyde (0.41 g, 2.5 mmole) for theethyl-indole-2-carboxylate, the title compound (0.24 g, 54%) wasprepared as a viscous oil: MS (ES) m/e 178 (M+H)⁺.

c) 4-Fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 11 (c), except substituting4-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.3 g, 1.69 mmole) for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.2 g,77%)was prepared as a viscous oil: MS (ES) m/e 193 (M+H)⁺.

Preparation 37 Preparation of(1-ethyl-5-fluoro-3-(methylaminomethyl)-1H-indole

a) 5-Fluoro-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 11 (b), except substituting5-fluoroindole (0.5 g, 3.7 mmole) for the 1,3-dimethylindole, the titlecompound (0.3 g, 50%) was prepared as a waxy solid: MS (ES) m/e164(M+H)⁺.

b) 1-Ethyl-5-fluoro-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 9 (a), except substituting5-fluoro-1H-indole-3-carboxaldehyde (0.41 g, 2.5 mmole) for theethylindole-2-carboxylate, the title compound (0.20 g, 57%) was preparedas a viscous oil: MS (ES) m/e 191 (M+H)⁺.

c) 1-Ethyl-5-fluoro-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 11 (c), except substituting1-ethyl-5-fluoro-1H-indole-3-carboxaldehyde (0.2 g,1.9 mmole) for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.1 g, 50%)was prepared as a viscous oil: MS (ES) m/e 207 (M+H)⁺.

Preparation 38 Preparation of4,6-dichloro-1-methyl-2-(methylaminomethyl)-1H-indole

a) Ethyl 4,6-dichloro-1-methyl-1H-indole-2-carboxylate

NaH (60% dispersion in mineral oil, 0.24 g, 6 mmole) was washed withhexanes, then was suspended in anhydrous DMF (16 mL). The mixture wascooled to 0° C., and ethyl 4,6-dichloroindole-2-carboxylate (1.03 g, 4mmole) was added. After 2–3 min, iodomethane (1.3 mL, 20 mmole) wasadded, and the mixture was warmed to RT. The mixture became thick, andstirring became difficult for several minutes. After 0.5 hr, thereaction was cooled to 0° C. and quenched with 10% NH₄Cl (2 mL). Themixture was concentrated to dryness, and the residue was partitionedbetween Et₂O (50 mL) and H₂O (10 mL). The layers were separated and theorganic layer was washed with H₂O (5 mL), dried (MgSO₄), and filtered,and the filter pad was washed with a little CH₂Cl₂. Concentrationafforded the title compound (1.06 g, 97%) as an off-white solid: ¹H NMR(400 MHz, CDCl₃) δ 7.34 (s, 1 H), 7.30 (s, 1 H), 7.17 (d, J=1.5 Hz, 1H), 4.39 (q, J=7.1 Hz, 2 H), 4.05 (s, 3 H), 1.42 (t, J=7.1 Hz, 3 H); MS(ES) m/e 272 and 274 (M+H)⁺.

b) N,1-Dimethyl-1H-indole-2-carboxamide

A suspension of ethyl 4,6-dichloro-1-methyl-1H-indole-2-carboxylate(1.06 g, 3.90 mmole) in 2.0 M CH₃NH₂/CH₃OH (40 mL) in a sealed pressurebottle was heated in an oil bath preset at 50° C. A homogeneous solutionformed within 2.5 hr. The reaction was kept at 50° C. for 17.5 hr,during which time a solid precipitated. The mixture was cooled to RT andpoured into H₂O (40 mL). The resulting mixture was concentrated on therotavap to remove the methanol, and the solid was collected by suctionfiltration. This was washed with plenty of H₂O and dried in high vacuumat 45–50° C. to afford the title compound (0.99 g, 99%) as an off-whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 7.29 (s, 1 H), 7.16 (d, J=1.5 Hz, 1 H),6.86 (s, 1 H), 6.21 (br s, 1 H), 4.02 (s, 3 H), 3.02 (d, J=4.9 Hz, 3 H);MS (ES) m/e257 and 259 (M+H)⁺.

c) 4,6-Dichloro-1-methyl-2-(methylaminomethyl)-1H-indole

A solution of 2.0 M BH₃.DMS in THF (3.6 mL, 7.2 mmole) was added to asolution of N,1-dimethyl-1H-indole-2-carboxamide (0.74 g, 2.88 mmole) inanhydrous THF (25 mL), and the reaction was heated at reflux. After 18hr, the reaction was cooled to 0° C. and quenched with MeOH (5 mL). Thesolution was warmed to RT, stirred for 0.5 hr, then concentrated on therotavap. The residue was re-concentrated from MeOH, then was purified byflash chromatography on silica gel (5% MeOH/CHCl₃ containing 0.5% conc.NH₄OH). The title compound (197.5 mg, 28%) was obtained as a whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 7.19 (dd, J=1.5, 0.8 Hz, 1 H), 7.09 (d,J=1.5 Hz, 1 H), 6.45 (s, 1 H), 3.88 (s, 2 H), 3.74 (s, 3 H), 2.50 (s, 3H); MS (ES) m/e 212 and 214 (M+H−CH₃NH₂)⁺.

Preparation 39 Preparation of1,7-dimethyl-3-(methylaminomethyl)-1H-indole

a) 1,7-Dimethyl-1H-indole

According to the procedure of Preparation 13 (a), except substituting7-methylindole for the 3-methylindole, the title compound (1.95 g, 90%)was obtained as a light-colored oil: MS (ES) mmole 146.2 (M+H)⁺.

b) 1,7-Dimethyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 13 (b), except substituting1,7-dimethylindole for the 1,2-dimethylindole, the title compound (1.85g, 82%) was obtained as an off white solid: MS (ES) m/e174.2 (M+H)⁺.

c) 1,7-Dimethyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 13 (c), except substituting1,7-dimethyl-1H-indole-3-carboxylate for the1,3-dimethyl-1H-indole-2-carboxylate, the title compound (0.74 g, 98%)was obtained as an amber oil: MS (ES) mmole 189.2 (M+H)⁺.

Preparation 40 Preparation of4-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

a) 4-Methoxy-1-methyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 13 (b), except substituting1-methyl-4-methoxyindole for the 1,2-dimethylindole, the title compound(2.17 g, 93%) was obtained as an off white solid: MS (ES) m/e 190.2(M+H)⁺.

b) 4-Methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 13 (c), except substituting1-methyl-4-methoxy-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.0 g, 95%)was obtained as a white solid: MS (ES) m/e 205.2 (M+H)⁺.

Preparation 41 Preparation of5-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

a) 5-Methoxy-1-methyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 13 (a), except substituting5-methoxy-1H-indole-3-carboxaldehyde for the3-methyl-1H-indole-3-carboxaldehyde, the title compound (0.86 g, 92%)was obtained as a light tan solid: MS (ES) m/e 190.2 (M+H)⁺.

b) 5-Methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 13 (c), except substituting5-methoxy-1-methyl-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.85 g,98%) was obtained as a light yellow oil: MS (ES) m/e 205.2 (M+H)⁺.

Preparation 42 Preparation of7-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

a) 7-Methoxy-1-methyl-1H-indole

According to the procedure of Preparation 13 (a), except substituting7-methoxyindole for 3-methylindole, the title compound (1.55 g, 96%) wasobtained as a tan solid: MS (ES) m/e 162.2 (M+H)⁺.

b) 7-Methoxy-1-methyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 13(b), except substituting7-methoxy-1-methyl-1H-indole for the 1,2-dimethylindole, the titlecompound (1.6 g, 91%) was obtained as an off white solid: MS (ES) m/e190.2 (M+H)⁺.

c) 7-Methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 13(c), except substituting7-methoxy-1-methyl-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (1.6 g, 94%)was obtained as an amber oil: MS (ES) m/e 205.2 (M+H)⁺.

Preparation 43 Preparation of7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole

a) 7-Chloro-1-methyl-1H-indole

According to the procedure of Preparation 13 (a), except substituting7-chloroindole for the 3-methylindole, the title compound (2.2 g, 100%)was obtained as a white solid: MS (ES) m/e 166.2 (M+H)⁺.

b) 7-Chloro-1-methyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 13 (b), except substituting7-chloro-1-methyl-1H-indole for the 1,2-dimethylindole, title compound(2.1 g, 84%) was obtained as a white solid: MS (ES) m/e 194.0 (M+H)⁺.

c) 7-Chloro-1-methyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 13 (c), except substituting7-chloro-1-methyl-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.0 g, 93%)was obtained as an amber oil: MS (ES) m/e 209.2 (M+H)⁺.

Preparation 44 Preparation of6-chloro-1-methyl-3-(methylaminomethyl)-1H-indole

a) 6-Chloro-1-methyl-1H-indole

According to the procedure of Preparation 13 (a), except substituting6-chloroindole for the 3-methylindole, the title compound (2.2 g, 100%)was obtained as a white solid: MS (ES) m/e 166.2.0 (M+H)⁺.

b) 6-Chloro-1-methyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 13 (b), except substituting6-chloro-1-methyl-1H-indole for the 1,2-dimethylindole, title compound(2.2 g, 88%) was obtained as an amber oil: MS (ES) m/e 194.2 (M+H)⁺.

c) 6-Chloro-1-methyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 13 (c), except substituting6-chloro-1-methyl-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.1 g, 93%)was obtained as an amber oil: MS (ES) m/e 209.2 (M+H)⁺.

Preparation 45 Preparation of5-chloro-1-methyl-3-(methylaminomethyl)-1H-indole

a) 5-Chloro-1-methyl-1H-indole

According to the procedure of Preparation 13 (a), except substituting5-chloroindole for the 3-methylindole, the title compound (2.0 g, 91%)was obtained as an amber oil: MS (ES) m/e 166.0 (M+H)⁺.

b) 5-Chloro-1-methyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 13 (b), except substituting5-chloro-1-methyl-1H-indole for the 1,2-dimethylindole, title compound(2.0 g, 83%) was obtained as an white solid: MS (ES) m/e 194.0′(M+H)⁺.

c) 5-Chloro-1-methyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 13 (c), except substituting5-chloro-1-methyl-1H-indole-3-carboxaldehyde for the,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.1 g, 93%)was obtained as an amber oil: MS (ES) m/e 209.0 (M+H)⁺.

Preparation 46 Preparation of4-chloro-1-methyl-3-(methylaminomethyl)-1H-indole

a) 4-Chloro-1-methyl-1H-indole

According to the procedure of Preparation 13 (a), except substituting4-chloroindole for the 3-methylindole, the title compound (2.2 g, 100%)was obtained as an amber oil: MS (ES) m/e 166.0 (M+H)⁺.

b) 4-Chloro-1-methyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 13 (b), except substituting4-chloro-1-methyl-1H-indole for the 1,2-dimethylindole, title compound(1.9 g, 76%) was obtained as an off-white solid: MS (ES) m/e 194.0(M+H)⁺.

c) 4-Chloro-1-methyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 13 (c), except substituting4-chloro-1-methyl-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (1.75 g,78%) was obtained as a yellow solid: MS (ES) m/e 209.0 (M+H)⁺.

Preparation 47 Preparation of1,1-dimethyl-3-(methylaminomethyl)-3H-indene

a) 1,1-Dimethyl-3H-indene-3-carboxaldehyde

The title compound was obtained in quantitative yield according toestablished literature procedures (Chem. Pharm. Bull. 1986, 34, 390–395;Tet. Lett. 1993, 34, 2979): ¹H NMR (400 MHz, CDCl₃) δ 10.05 (s, 1 H),8.05 (d, 2 H), 7.35 (m, 4 H), 1.40 (s, 6 H).

b) 1,1-Dimethyl-3-(methylaminomethyl)-3H-indene

According to the procedure of Preparation 12, except substituting1,1-dimethyl-3H-indene-3-carboxaldehyde for the2-methylindole-3-carboxaldehyde, the title compound (3 g, 81%) wasobtained as a reddish oil: MS (ES) m/e 188.2 (M+H)⁺.

Preparation 48 Preparation of7-hydroxy-1-methyl-3-(methylaminomethyl)-1H-indole

a) 7-Benzyloxy-1-methyl-1H-indole

According to the procedure of Preparation 13 (a), except substituting7-benzyloxyindole for the 3-methylindole, the title compound (4.8 g,100%) was obtained as an amber oil: MS (ES) m/e 238.0 (M+H)⁺.

b) 7-Benzyloxy-1-methyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 13 (b), except substituting7-benzyloxy-1-methyl-1H-indole for the 1,2-dimethylindole, titlecompound (4.5 g, 85%) was obtained as an oil: MS (ES) m/e 266.0 (M+H)⁺.

c) 7-Benzyloxy-1-methyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 13 (c), except substituting7-benzyloxy-1-methyl-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (3.7 g, 88%)was obtained as an oil: MS (ES) m/e 281.2 (M+H)⁺.

d) 7-Hydroxy-1-methyl-3-(methylaminomethyl)-1H-indole

According to the literature procedure (J. Org. Chem. 1978, 43, 4195–96),7-benzyloxy-1-methyl-3-(methylaminomethyl)-1H-indole was hydrogenated toafford the title compound (300 mg, 79%) as a brown solid: MS (ES) m/e191.2 (M+H)⁺.

Preparation 49 Preparation of3-(methylaminomethyl)-1,2,7-trimethyl-1H-indole

a) 1,2,7-Trimethyl-1H-indole

According to the procedure of Preparation 13 (a), except substituting2,7-dimethylindole for the 3-methylindole, the title compound (960 mg,87%) was obtained as an oil: MS (ES) m/e 160.2 (M+H)⁺.

b) 1,2,7-Trimethylindole-3-carboxaldehyde

According to the procedure of Preparation 13 (b), except substituting1,2,7-trimethyl-1H-indole for the 1,4-dimethylindole, the title compound(800 mg, 62%) was obtained as a light tan solid: MS (ES) m/e 188.2(M+H)⁺.

c) 3-(Methylaminomethyl)-1,2,7-trimethyl-1H-indole

According to the procedure of Preparation 13 (c) except substituting1,2,7-trimethyl-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (570 mg,71%) was obtained as an oil which slowly crystallized: MS (ES) m/e 405.4(2M+H)⁺.

Preparation 50 Preparation of 7-chloro-3-(methylaminomethyl)-1H-indole

a) 7-Chloro-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 13 (b), except substituting7-chloroindole for the 1,2-dimethylindole, the title compound (0.48 g,44%) was obtained as a white solid after recrystallization from hotEtOAc: MS (ES) m/e 180.0 (M+H)⁺.

b) 7-Chloro-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 13 (c), except substituting7-chloro-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (440 mg,92%) was obtained as an off white solid: MS (ES) m/e 195.2 (M+H)⁺.

Preparation 51 Preparation of 2-(methylaminomethyl)naphthalene

To a stirred solution of 40 wt % methylamine in H₂O (50 mL, 581 mmole)in THF (50 mL) at 0° C. was added 2-(bromomethyl)naphthalene (10 g, 43mmole) in one portion. The reaction was allowed to warm to RT andstirred for 16 hr, then was then concentrated under vacuum. The residuewas taken up in Et₂O and washed with 1.0 N NaOH then with brine, dried(Na₂SO₄), and concentrated to dryness. Purification by flashchromatography on silica gel (98:2 to 9:1 CHCl₃/methanol containing 5%NH₄OH) gave the title compound (3.95 g, 54%) as a clear oil: ¹H NMR (400MHz, CDCl₃) δ 7.85 (m, 3 H), 7.79 (s, 1 H), 7.49 (m, 3 H), 3.94 (s, 2H), 2.53 (s, 3 H).

Preparation 52 Preparation of 3-(methylaminomethyl)quinoline

A solution of 3-quinolinecarboxaldehyde (1.5 g,10 mmole), 2.0 MCH₃NH₂/MeOH (10 mL, 20 mmole), glacial AcOH (0.6 mL, 10 mmole), andNaBH₃CN (0.35 g, 11 mmole) in MeOH (20 mL) was stirred at RT overnight,then was concentrated in vacuo. The residue was diluted with 5% NaOH andextracted with CH₂Cl₂. The combined organic extracts were washed withbrine, dried over MgSO₄, and concentrated. Flash chromatography onsilica gel (10% MeOH/CH₂Cl₂) gave the title compound (0.83 g, 24%) as aslightly yellow viscous oil: MS (ES) m/e 173 (M+H)⁺.

Preparation 53 Preparation of(E)-2-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1.8-naphthyridin-3-yl)acrylicacid hydrochloride salt

a) tert-Butyl(E)-2-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate

According to the procedure of Preparation 31 (a), except substitutingtert-butyl methacrylate (4.7 g, 33.2 mmole) for the tert-butyl acrylate,the title compound (2.7 g, 42 %) was prepared as a yellow solid: MS (ES)m/e 289 (M+H)⁺.

b)(E)-2-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylicacid hydrochloride salt

According to the procedure of Preparation 31 (b), except substitutingtert-butyl(E)-2-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate(2.7 g, 9.3 mmole) for the tert-butyl(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate, thetitle compound (2.5 g, 99%) was prepared as a white solid: MS (ES) m/e232 (M+H)⁺.

Preparation 54 Preparation of(E)-3-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylicacid hydrochloride salt

a) tert-Butyl(E)-3-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate

According to the procedure of Preparation 31 (a), except substitutingtert-butyl crotonate (4.7 g, 33.2 mmole) for the tert-butyl acrylate,the title compound (3.7 g, 58%) was prepared as a yellow solid: MS (ES)m/e 289 (M+H)⁺.

b)(E)-3-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylicacid hydrochloride salt

According to the procedure of Preparation 31 (b), except substitutingtert-butyl(E)-3-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate(3.7 g, 12.8 mmole) for the tert-butyl(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate, thetitle compound (3.4 g, 99%) was prepared as a white solid: MS (ES) m/e232 (M+H)⁺.

Preparation 55 Preparation of7-bromo-4-methyl-1,2,4,5-tetrahydropyrido[2,3-e]-1,4-diazepin-3-one

a)5-Bromo-3-[N-(tert-butoxycarbonyl)-N-methylaminomethyl]-2-[N-(tert-butoxycarbonyl)amino]pyridine

To a solution of 2-amino-5-bromo-3-(methylaminomethyl)pyridine (3.8 g,17.6 mmole), from Preparation 5 (a), in THF was added di-tert-butyldicarbonate (8.8 g, 40.5 mmole). The reaction was heated to reflux for12 hr then was concentrated under vacuum. Flash chromatography on silicagel (1:1 hexanes/EtOAc) gave the title compound (6.2 g, 85%) as a whitewaxy solid: MS (ES) m/e 416 (M+H)⁺.

b)5-Bromo-2-[(ethoxycarbonyl)methylamino]-3-(methylaminomethyl)-2-[N-(tert-butoxycarbonyl)amino]PyridineBis-trifluoroacetic acid salt

To a suspension of 60% NaH (0.46 g, 11.5 mmole) in THF (100 mL) at RTwas added5-bromo-3-[N-(tert-butoxycarbonyl)-N-methylaminomethyl]-2-[N-(tert-butoxycarbonyl)amino]pyridine(4.0 g, 9.61 mmole). After 30 min, ethyl bromoacetate (1.8 g, 10.6mmole) was added. The reaction was stirred at RT for 12 hr, then wasquenched with H₂O (5 mL) and concentrated. The residue was dissolved inEtOAc (200 mL), and the solution was washed with H₂O (100 mL), driedover Na₂SO₄, and concentrated under high vacuum to a light yellow solid.This was dissolved in CH₂Cl₂ (50 mL) and trifluoroacetic acid (20 mL).After 2 hr, the reaction was concentrated under vacuum and the residuewas purified flash chromatography on silica gel (95:5 CHCl₃/CH₃OH). Thetitle compound (4.1 g, 80%) was obtained as a yellow solid: MS (ES)m/e302 (M+H)⁺.

c) 7-Bromo4-methyl-1,2,4,5-tetrahydropyrido[2,3-e]-1,4-diazepin-3-one

To a solution of5-bromo-2-[(ethoxycarbonyl)methylamino]-3-(methylaminomethyl)-2-[N-(tert-butoxycarbonyl)amino]pyridinebis-trifluoroacetic acid salt (4.1 g, 7.7 mmole) in toluene was addedtriethylamine (3.3 mL, 23.7 mmole). The reaction was heated at refluxfor 72 hr then concentrated under vacuum. Flash chromatography on silicagel (9:1 CHCl₃/CH₃OH containing 5% NH₄OH) gave the title compound (1.4g, 72%) as a tan solid: MS (ES) m/e 256 (M+H)⁺.

Preparation 56 Preparation of(E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-acrylicacid hydrochloride salt

a) tert-butyl(E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylate

A solution of 3-bromo-5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one (1.00g, 4.15 mmole), tert-butyl acrylate (0.67 mL, 4.60 mmole), DIEA (1.45mL, 8.30 mmole), Pd(OAc)₂ (0.09 g, 0.42 mmole) and P(o-tol)₃ (0.25 g,0.85 mmole) in propionitrile (25 mL) was purged with N₂ and then heatedat reflux overnight. The dark mixture was filtered through a pad ofcelite®, and the filter pad was rinsed with acetonitrile (250 mL). Thefiltrate was concentrated in vacuo, and the residue was purified byflash chromatography on silica gel (ethyl acetate). The title compound(0.70 g, 58%) was obtained as a light yellow solid after drying invacuo: MS (ES) m/e 289 (M+H)⁺.

b) (E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-acrylicacid hydrochloride salt

According to the procedure of Preparation 31 (b), except substitutingtert-butyl(E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylate(0.70 g, 2.40 mmole) for the tert-butyl(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate, thetitle compound (0.49 g, 77%) was obtained as an off-white solid afterdrying in vacuo: MS (ES) m/e 233 (M+H)⁺.

Preparation 57 Preparation of1-(2-hydroxyethyl)-3-(methylaminomethyl)-1H-indole

According to the reported literature procedure (J. Org. Chem. 1998, 63,6721–6726) except substituting3-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole (3.70 g, 12.60mmole) for the 5-bromoindole, the title compound (4.00 g, 93%) wasobtained as a yellow solid after drying in vacuo: MS (ES) m/e 338(M+H)⁺.

Preparation 58 Preparation of2-chloro-1-methyl-2-(methylaminomethyl)-1H-indole

a) 2-Chloro-1H-indole-3-carboxaldehyde

To DMF (30 mL) with stirring at 0° C. was added dropwise phosphorusoxychloride (10 mL, 107 mmole) over 5 minutes. The reaction was stirredfor an additional 15 minutes, then oxindole (6.0 g, 45 mmole) was addedportionwise over 5 min. The reaction was allowed to warm to RT andstirred for 18 h then was carefully poured into ice water (350 mL). Thesolution was stirred for 6 h after which time a suspension formed. Thesolids were filtered off, washed with cold water, pressed dry and driedunder vacuum to give the title compound (6.83 g, 84%) as a yellowishsolid: ¹H NMR (400 MHz, d₆-DMSO) δ 10.0 (s, 1 H), 8.05 (dd, 1 H), 7.43(dd, 1 H), 7.23–7.31 (m, 2 H); MS (ES) m/e 179.0 (M+H)⁺.

b) 2-Chloro-1-methyl-1H-indole-3-carboxaldehyde

NaH (60% dispersion in mineral oil) (0.9 g, 22.5 mmole) was addedportionwise over 5 min to a solution of2-chloro-1H-indole-3-carboxaldehyde (3.8 g, 21.2 mmole) and iodomethane(1.5 mL, 24 mmole) in DMF (50 mL) with stirring at 0° C. The reactionwas allowed to warm to RT and stir for 4 h, then was concentrated undervacuum. The remaining residue was taken up in EtOAc, and the solutionwas washed with water then brine, dried (MgSO₄), and concentrated todryness. Trituration with 1:1 Et₂O/petroleum ether, filtration, anddrying under vacuum gave the title compound (3.10 g, 76%) as anoff-white solid: ¹H NMR (400 MHz, CDCl₃) δ 10.12 (s, 1 H), 8.29 (m, 1H), 7.33 (m, 3 H), 3.81 (s, 3 H); MS (ES) m/e 194.0 (M+H)⁺.

c) 2-Chloro-1-methyl-2-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 12, except substituting2-chloro-1-methyl-1H-indole-3-carboxaldehyde (3.0 g, 15.5 mmole) for the1-methylindole-3-carboxaldehyde, the title compound (2.91 g, 90%) wasprepared as an oil: ¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J=7.9 Hz, 1 H),7.22 (m, 2 H), 7.13 (m, 1 H), 3.92 (s, 2 H), 3.71 (s, 3 H), 2.44 (s, 3H).

Preparation 59 Preparation of3-(benzhydrylideneamino)-6-bromo-3,4-dihydro-1H-1.8-naphthyridin-2-one

NaH (60% dispersion in mineral oil, 1.2 g, 30 mmole) was addedportionwise over 10 min to a solution of N-(diphenylmethylene)glycineethyl ester (8.0 g, 30 mmole) in DMF (150 mL) with stirring under Ar at0° C. The reaction was stirred for 15 min, then2-amino-5-bromo-3-(bromomethyl)pyridine hydrobromide (5.0 g, 14.4 mmole)was added in one portion. The reaction was allowed to warm to RT andstir for 18 h, then was concentrated under vacuum. The remaining residuewas taken up in EtOAc (150 mL), hexane (150 mL), and H₂O (150 mL). Theresulting suspension was triturated and filtered, and the solid wasdried under vacuum to give the title compound (3.27 g, 56%) as anoff-white solid: ¹H NMR (400 MHz, d₆-DMSO) δ 10.92 (s, 1 H), 8.23 (s, 1H), 7.86 (s, 1 H), 7.26–7.55 (m, 10 H), 4.05 (dd, 1 H), 3.10 (t, 2 H);MS (ES) m/e 406.0 (M+H)⁺.

Preparation 60 Preparation of 2-(methylaminomethyl)benzofuran

To a stirred solution of 2-benzofurancarboxaldehyde (2.22 g, 15.2 mmole)in MeOH (5 mL) was added 2 M methylamine in MeOH (15 mL), HOAc (0.86 mL,15 mmole), and NaBH₃CN (1.0 g, 15.9 mmole). The reaction was stirred for18 h at RT then concentrated under vacuum. The remaining residue wastaken up in Et₂O, and the solution was washed with 1 N NaOH then brine,dried (Na₂SO₄), and concentrated to dryness. Purification by flashchromatography on silica gel (5% (5% NH₄OH in MeOH)/CHCl₃) gave thetitle compound (1.23 g, 50%) as a pale yellow oil: MS (ES) m/e 162.4(M+H)⁺.

Preparation 61 Preparation of methyl1-methyl-3-(methylaminomethyl)-1H-indole-7-carboxylate

a) Methyl 1-methyl-1H-indole-7-carboxylate

According to the procedure of Preparation 9 (a), except substitutingmethyl indole-7-carboxylate for the ethyl indole-2-carboxylate, thetitle compound (2.4 g, 90%) was obtained as an oil: MS (ES) m/e 190.2(M+H)⁺.

b) N-Methyl-7-methoxycarbonyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 13 (b), except substitutingmethyl 1-methyl-1H-indole-7-carboxylate for the 1,3-dimethylindole, thetitle compound (1.8 g, 70%) was obtained as a white solid: MS (ES) m/e218.2 (M+H)⁺.

c) Methyl 1-methyl-3-(methylaminomethyl)-1H-indole-7-carboxylate

According to the procedure of Preparation 12, except substituting1-methyl-7-methoxycarbonyl-1H-indole 3-carboxaldehyde for the2-methylindole-3-carboxaldehyde, the title compound (1.7 g, 92%) wasobtained as an oil: MS (ES) m/e 233.2 (M+H)⁺.

Preparation 62 Preparation of methyl1-methyl-3-(methylaminomethyl)-1H-indole-6-carboxylate

a) Methyl 1-methyl-1H-indole-6-carboxylate

According to the procedure of Preparation 9 (a), except substitutingmethyl indole-6-carboxylate for the ethyl indole-2-carboxylate, thetitle compound (2.5 g, 95%) was obtained as white solid: MS (ES) m/e190.2 (M+H)⁺.

b) N-Methyl-7-methoxycarbonyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 13 (b), except substitutingmethyl 1-methyl-1H-indole-6-carboxylate for the 1,3-dimethylindole, thetitle compound (2.6 g, 98%) was obtained as a white solid: MS (ES) m/e218.2 (M+H)⁺.

c) Methyl 1-methyl-3-(methylaminomethyl)-1H-indole-6-carboxylate

According to the procedure of Preparation 12, except substituting1-methyl-7-methoxycarbonyl-1H-indole 3-carboxaldehyde for the2-methylindole-3-carboxaldehyde, the title compound (1.9 g, 63%) wasobtained as an oil: MS (ES) m/e 233.2 (M+H)⁺.

Preparation 63 Preparation of6-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

a) 6-Methoxy-1-methyl-1H-indole

According to the procedure of Preparation 9 (a), except substituting6-methoxy-1H-indole for the ethyl indole-2-carboxylate, the titlecompound (2.3 g, 95%) was obtained as an oil: MS (ES) m/e 162.2 (M+H)⁺.

b) 6-Methoxy-1-methyl-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 13 (b), except substituting6-methoxy-1-methyl-1H-indole for the 1,3-dimethylindole, the titlecompound (2.3 g, 82%) was obtained as a tan solid: MS (ES) m/e 190.2(M+H)⁺.

c) 6-Methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 12, except substituting6-methoxy-1-methyl-1H-indole-3-carboxaldehyde for the2-methylindole-3-carboxaldehyde, the title compound (2.1 g, 87%) wasobtained as an oil: MS (ES) m/e 205.2 (M+H)⁺.

Preparation 64 Preparation of 7-fluoro-3-(methylaminomethyl)-1H-indole

a) 7-Fluoro-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 13 (b), except substituting7-fluoroindole (0.5 g, 3.7 mmole) for the 1,3-dimethylindole, the titlecompound (0.3 g, 55%) was prepared as a waxy solid: MS (ES) m/e 164(M+H)⁺.

b) 7-Fluoro-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 13 (c),except substituting7-fluoro-1H-indole-3-carboxaldehyde (0.5 g, 3.1 mmole) for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.5 g, 90%)was prepared as a viscous oil: MS (ES) m/e 179 (M+H)⁺.

Preparation 65 Preparation of 4-fluoro-3-(methylaminomethyl)-1H-indole

a) 4-Fluoro-1H-indole-3-carboxaldehyde

According to the procedure of Preparation 13 (b), except substituting4-fluoroindole (0.4 g, 2.45 mmole) for the 1,3-dimethylindole, the titlecompound (0.31 g, 72%) was prepared as a viscous oil: MS (ES) m/e 164(M+H)⁺.

b) 4-Fluoro-3-(methylaminomethyl)-1H-indole

According to the procedure of Preparation 13 (c),except substituting4-fluoro-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound was preparedas a viscous oil: MS (ES) m/e 179 (M+H)⁺.

Preparation 66 Preparation of6-bromo-3-(2-methoxyethyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

a) 2-Amino-5-bromo-3-[(2-methoxyethyl)aminomethyl]pyridine

2-Methoxyethylamine (1.49 mL, 17.16 mmole) was added to a solution of2-amino-5-bromo-3-(bromomethyl)pyridine hydrobromide (1.49 g, 4.29mmole) and DIEA (2.24 mL, 12.87 mmole) in CH₂Cl₂ (10 mL) at RT. Thereaction was stirred overnight then was concentrated in vacuo. Theresidue was diluted with water and the solution was extracted with ethylacetate. The combined organic extracts were washed with brine, driedover Na₂SO₄, and concentrated to afford the title compound (1.00 g, 90%)as a light brown liquid after drying in vacuo: MS (ES) m/e 260/262(M+H)⁺.

b)6-Bromo-3-(2-methoxyethyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

1,1′-Carbonyldiimidazole (0.74 g, 4.60 mmole) was added to a solution of2-amino-5-bromo-3-[(2-methoxyethyl)aminomethyl]pyridine (1.00 g, 3.80mmole) in 1,2-dichloroethane (35 mL) at RT. The reaction was heated at65° C. with stirring overnight, then was concentrated in vacuo. Flashchromatography on silica gel (5% MeOH/(CHCl₃) gave title compound (0.90g, 83%) as a yellow solid after drying in vacuo: MS (ES) m/e 286/288(M+H)⁺.

The following examples illustrate methods for preparing the biologicallyactive compounds of this invention from intermediate compounds such asthose described in the foregoing Preparations.

Example 1 Preparation of(E)-3-(2-aminopyrimidin-5-yl)-N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

a) N-Methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide

To a solution of 2-methyl-3-(methylaminomethyl)indole (1.5 g, 8.6 mmole)and triethylamine (1.7 g, 17.3 mmole) in CH₂Cl₂ at 5° C. under anitrogen atmosphere was added acryloyl chloride (0.86 g, 9.48 mmole).After 1 hr the reaction solution was poured into H₂O (100 mL) and thelayers were separated. The organic fraction was washed with H₂O (100 mL)followed by brine and then dried over Na₂SO₄. Concentration under vacuumgave the title compound as an orange oil which solidified under highvacuum: MS (ES) m/e 457 (2M+H)⁺. This material was used without furtherpurification.

b)(E)-3-(2-Aminopyrimidin-5-yl)-N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

A solution of N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide (1.18g, 6.5 mmole), 2-amino-5-bromopyrimidine (0.5 g, 2.9 mmole), Pd(OAc)₂(0.11 g, 0.49 mmole), tri-ortho-tolylphosphine (0.17 g, 0.55 mmole), anddiisopropylethylamine (1.5 mL, 8.6 mmole) in propionitrile (100 mL) andDMF (10 mL) was heated at reflux overnight. The dark mixture wasfiltered through celite®, and the filtrate was concentrated. Flashchromatography on silica gel (9:1 CHCl₃/CH₃OH containing 5% NH₄OH) gavethe title compound (1.2 g, 65%): MS (ES) m/e 372 (M+H)⁺.

Example 2 Preparation of(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylamide

According to the procedure of Example 1 (b), except substituting6-bromo-3-methyl-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one (1.2 g, 5.0mmole) for the 2-amino-5-bromopyrimidine, the title compound (73%) wasprepared as a light yellow solid: MS (ES) m/e 390 (M+H)⁺.

Example 3 Preparation of(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylamide

a) N-Methyl-N-(1-methyl-indol-3-ylmethyl)acrylamide

According to the procedure of Example 1 (a), except substituting1-methyl-3-(methylaminomethyl)indole for the2-methyl-3-(methylaminomethyl)indole, the title compound (1.7 g, 99%)was prepared as an orange oil that solidified under vacuum: MS (ES) m/e229 (M+H)⁺. This material was used without further purification.

b)(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylamide

According to the procedure of Preparation 1 (b), except substitutingN-methyl-N-(1-methyl-indol-3-ylmethyl)acrylamide (1.7 g, 7.5 mmole) forN-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide, the title compound(70%) was prepared as a light yellow solid: MS (ES) m/e 390 (M+H)⁺.

Example 4 Preparation of(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide

To a solution of (E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acidhydrochloride salt (0.50 g, 2.1 mmole), hydroxybenzotriazole monohydrate(0.31 g, 2.3 mmole), diisopropylethylamine (0.80 mL, 4.6 mmole), and2-methyl-3-(methylaminomethyl)indole (0.40 g, 2.3 mmole) in DMF (50 mL)at RT was added EDC (0.46, 2.3 mmole). After 12 hr the reaction solutionwas concentrated under vacuum and the residue was purified by flashchromatography on silica gel (9:1 CHCl₃/CH₃OH containing 5% NH₄OH) togive the title compound (0.66 g, 88%) as a light yellow solid: MS (ES)m/e 361 (M+H)⁺.

Example 5 Preparation of(E)-3-(3H-imidazo[4,5-b]pyridin-6-yl)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)acrylamide

According to the procedure of Example 4, except substituting(E)-3-(3H-imidazo[4,5-b]pyridin-6-yl) acrylate (0.14 g, 0.74 mmole),from Preparation 6, for the(E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt,and substituting 1-methyl-3-(methylaminomethyl)indole (0.14 g, 0.81mmole) for the 2-methyl-3-(methylaminomethyl)-1H-indole, the titlecompound (0.23 g, 89%) was prepared as a light yellow solid: MS (ES) m/e346 (M+H)⁺.

Example 6 Preparation of(E)-3-(3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-7-yl)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)acrylamide

According to the procedure of Example 4, except substituting(E)-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid (0.11g, 0.53 mmole), from Preparation 7, for the(E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt,and substituting 1-methyl-3-(methylaminomethyl) indole (0.10 g, 0.59mmole) for the 2-methyl-3-(methylaminomethyl)-1H-indole, the titlecompound (0.16 g, 82%) was prepared as a light yellow solid: MS (ES)m/e363 (M+H)⁺.

Example 7 Preparation of(E)-3-[6-amino-5-[[N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)amino]carbonylethyl]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide

a) Ethyl (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) acrylate

A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (5.0 g, 21.9mmole), from Preparation 4, ethyl acrylate (3.3 g, 32.9 mmole), Pd(OAc)₂(1.1 g, 0.74 mmole), tri-ortho-tolylphosphine (1.3 g, 4.4 mmole), anddiisopropylethylamine (11.4 mL, 65.7 mmole) in propionitrile (200 mL)and DMF (25 mL) was heated at reflux overnight. The dark mixture wasfiltered through celite®, and the filtrate was concentrated. Flashchromatography on silica gel (9:1 CHCl₃/CH₃OH containing 5% NH₄OH) gavethe title compound (3.0 g, 59%) as a light yellow solid: MS (ES) m/e 233(M+H)⁺.

b) (E)-3-[6-Amino-5-(2-carboxyethyl)pyridin-3-yl]acrylic acidhydrochloride salt

Ethyl (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) acrylate(1.54 g, 6.6 mmole) was dissolved in acetic acid (25 mL) andconcentrated hydrochloric acid (25 mL) and the solution was heated to100° C. After 6 hr the solution was concentrated and the residue wasdried under high vacuum. The resulting solid was triturated with diethylether and filtered to give a 1.46 g of a mixture of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) acrylic acidhydrochloride salt (82%) and the title compound (18%), both as whitesolids: MS (ES) m/e 218 (M+H)+(major) and MS (ES) m/e 236 (M+H)⁺(minor). This mixture was used without further purification.

c)(E)-3-[6-Amino-5-[[N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)amino]carbonylethyl]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide

According to the procedure of Example 4, except substituting a mixture(1.46 g) of (E)-3-[6-amino-5-(2-carboxyethyl)pyridin-3-yl]acrylic acidhydrochloride salt and(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) acrylic acidhydrochloride salt for the(E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt,the title compound (0.47 g) was prepared as a light yellow solid: MS(ES) m/e 549 (M+H)⁺.(E)-N-Methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide(1.56 g) was also obtained as a light yellow solid: MS (ES) m/e 375(M+H)⁺.

Example 8 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(1-ethyl-1H-indol-3-ylmethyl)-N-methylacrylamide

EDC (0.56 g, 2.93 mmole) was added to a solution of(E)-3-(6-aminopyridin-3-yl)acrylic acid (0.48 g, 2.93 mmole),1-ethyl-3-(methylaminomethyl)-1H-indole (0.50 g. 2.66 mmole), HOBt H₂O(0.40 g, 2.93 mmole) and diisopropylethylamine (0.93 mL, 5.32 mmole) inDMF (30 mL) at RT. The reaction was stirred overnight then wasconcentrated in vacuo. The residue was diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed with brineand dried over Na₂SO₄. Flash chromatography on silica gel (10%MeOH/CHCl₃) gave title compound (0.46 g, 52%) as a yellow solid afterdrying in vacuo: MS (ES) m/e 335 (M+H)⁺.

Example 9 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(1-isopropyl-1H-indol-3-ylmethyl)-N-methylacrylamide

EDC (0.51 g, 2.64 mmole) was added to a solution of(E)-3-(6-aminopyridin-3-yl)acrylic acid (0.43 g, 2.64 mmole),1-isopropyl-3-(methylaminomethyl)indole (0.49 g, 2.40 mmole), HOBt.H₂O(0.36 g, 2.64 mmole) and diisopropylethylamine (0.84 mL 4.80 mmole) inDMF (40 mL) at RT. The reaction was stirred overnight then wasconcentrated in vacuo. The residue was diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed with brineand dried over Na₂SO₄. Flash chromatography on silica gel (10%MeOH/CHCl₃) gave the title compound (0.49 g, 58%) as a yellow solidafter drying in vacuo: MS (ES) m/e 349 (M+H)⁺.

Example 10 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(1H-indol-3-ylmethyl)-N-methylacrylamide

EDC (1.03 g, 5.40 mmole) was added to a solution of(E)-3-(6-aminopyridin-3-yl)acrylic acid (0.89 g, 5.40 mmole),1-acetyl-3-(methylaminomethyl)indole (1.00 g, 4.95 mmole), HOBt.H₂O(0.73 g.,5.40 mmole) and diisopropylethylamine (1.72 mL, 9.90 mmole) inDMF (50 mL) at RT. The reaction was stirred overnight then wasconcentrated in vacuo. The residue was diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed with brineand dried over Na₂SO₄. Flash chromatography on silica gel (5%MeOH/CHCl₃) gave the title compound (0.90 g, 52%) as a light yellowsolid after drying in vacuo: MS (ES) m/e 307 (M+H)⁺.

Example 11 Preparation of(E)-N-(1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (0.64 g,2.80 mmole), N-(1H-indol-3-ylmethyl)-N-methylacrylamide (0.60 g, 2.80mmole), Pd(OAc)₂ (0.06 g, 0.28 mmole), tri-ortho-tolylphosphine (0.17 g,0.56 mmole) and diisopropylethylamine (0.73 mL, 4.2 mmole) inpropionitrile (50 mL) was deoxygenated, then was heated to reflux underN₂ overnight. The dark mixture was filtered through a pad of celite®,and the filter pad was rinsed with acetonitrile (250 mL). The filtratewas concentrated in vacuo, and the residue was purified by flashchromatography on silica gel (10% MeOH/CHCl₃). The title compound (0.37g, 37%) was obtained as a light yellow solid after drying in vacuo: MS(ES) m/e 361 (M+H)⁺.

Example 12 Preparation of(E)-N-(1-benzyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (1.05 g,4.60 mmole), N-(1-benzyl-1H-indol-3-ylmethyl)-N-methyl-acrylamide (1.40g, 4.60 mmole), Pd(OAc)₂ (0.10 g, 0.46 mmole), tri-ortho-tolylphosphine(0.28 g, 0.92 mmole) and diisopropylethylamine (1.20 mL 6.90 mmole) inpropionitrile (75 mL) was deoxygenated, then was and heated to refluxunder a N₂ overnight. The dark mixture was filtered through a pad ofcelite®, and the filter pad was rinsed with acetonitrile (300 mL). Thefiltrate was concentrated in vacuo, and the residue was purified byflash chromatography on silica gel (5% MeOH/CHCl₃). The title compound(0.70 g. 35%) was obtained as a light yellow solid after drying invacuo: MS (ES) m/e 451 (M+H)⁺.

Example 13 Preparation of(E)-N-[1-(2-dimethylaminoethyl)-1H-indol-3-ylmethyl]-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (0.61 g,2.70 mmole),N-[1-(2-dimethylaminoethyl)-1H-indol-3-ylmethyl]-N-methyl-acrylamide(1.00 g, 3.50 mmole), Pd(OAc)₂ (0.08 g, 0.35 mmole),tri-ortho-tolylphosphine (0.21 g, 0.70 mmole), and diisopropylethylamine(0.91 mL, 5.25 mmole) in propionitrile (70 mL) was deoxygenated, thenwas and heated to reflux under a N₂ overnight. The dark mixture wasfiltered through a pad of celite®, and the filter pad was rinsed withacetonitrile (250 mL). The filtrate was concentrated in vacuo, and theresidue was purified by flash chromatography on silica gel (10%MeOH/CHCl₃ containing 5% NH₄OH in the MeOH). The title compound (0.20 g.13%) was obtained as a light yellow solid after drying in vacuo: MS (ES)m/e432 (M+H)⁺.

Example 14 Preparation of(E)-N-methyl-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide

A solution of 3-bromo-5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one (0.60g, 2.50 mmole), N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide(0.85 g, 3.75 mmole), Pd(OAc)₂ (0.06 g, 0.25 mmole),tri-ortho-tolylphosphine (0.15 g, 0.50 mmole) and diisopropylethylamine(0.87 mL, 5.00 mmole) in propionitrile (50 mL) was deoxygenated, thenwas and heated to reflux under a N₂ overnight. The dark mixture wasfiltered through a pad of celite®, and the filter pad was rinsed withacetonitrile (200 mL). The filtrate was concentrated in vacuo, and theresidue was purified by flash chromatography on silica gel (10%MeOH/CHCl₃). The title compound (0.35 g. 35%) was obtained as a lighttan solid after drying in vacuo: MS (ES) m/e 246 (M+H)⁺.

Example 15 Preparation of(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-[6-(pyridin-2-ylamino)pyridin-3-yl]acrylamide

a) N-(1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

To a stirred solution of 1-methyl-3-(methylaminomethyl)-1H-indole (1.0g, 5.7 mmole) and Et₃N (0.8 mL, 5.7 mmole) in CH₂Cl₂ (50 mL) at 0° C.was added acryloyl chloride (0.47 mL, 5.8 mmole) in one portion. Afterstirring for 1 h the reaction was washed with cold H₂O and brine, thenwas dried (MgSO₄) and concentrated under vacuum. This material was usedwithout further purification.

b)(E)-N-Methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-[6-(pyridin-2-ylamino)pyridin-3-yl]acrylamide

To a solution of N-(1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide,from Example 1 (a), in propionitrile (50 mL) was added5-bromo-2,2′-dipyridylamine (1.2 g, 4.8 mmole), DIEA (1.8 mL, 10.3mmole), Pd(OAc)₂ (112 mg, 0.5 mmole), and P(o-tol)₃ (304 mg, 1 mmole).The reaction was purged with Ar then stirred at reflux for 16 h. Aftercooling to room temperature the reaction was concentrated to drynessunder vacuum. Flash chromatography on silica gel (3% (5%NH₄OH/MeOH)/CHCl₃), trituration with 1:1 Et₂O/petroleum ether,filtration, and drying under vacuum gave the title compound (1.24 g,65%) as an off-white solid: MS (ES) m/e 398.2 (M+H)⁺.

Example 16 Preparation of(E)-N-methyl-N-(2-methylbenzo[b]thiophen-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

a) N-(Benzo[b]thiophen-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 15 (a), except substituting2-methyl-3-(methylaminomethyl)benzo[b]thiophene (1.0 g, 5.2 mmole) for1-methyl-3-(methylaminomethyl)-1H-indole, the title compound wasprepared. This was used without further purification.

b)(E)-N-Methyl-N-(2-methylbenzo[b]thiophen-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 15 (b), except substituting6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (1.3 g, 5.7 mmole) for the5-bromo-2,2′-dipyridylamine, the title compound (0.849 g, 42%) wasprepared as a white solid: MS (ES) m/e 392.2 (M+H)⁺.

Example 17 Preparation of(E)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide

a) N-(1-methyl-1H-indol-2-ylmethyl)-N-methylacrylamide

According to the procedure of Example 15 (a), except substituting1-methyl-2-(methylaminomethyl)-1H-indole (1.2 g, 6.9 mmole) for the1-methyl-3-(methylaminomethyl)-1H-indole, the title compound wasprepared. This was used without further purification.

b)(E)-N-Methyl-N-(1-methyl-1H-indol-2-ylmethyl)-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide

According to the procedure of Example 15 (b), except substituting5-bromo-2-(methylaminocarbonylmethyl)aminopyridine (1.5 g, 6.2 mmole)for the 5-bromo-2,2′-dipyridylamine, the title compound (1.7 g, 72%) wasprepared as a white solid: MS (ES) m/e 392.2 (M+H)⁺.

Example 18 Preparation of(E)-3-(6-amino-5-(methoxycarbonyl)pyridin-3-yl)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

a) N-(1-methyl-1H-indol-2-ylmethyl)-N-methylacrylamide

According to the procedure of Example 15 (a), except substituting1-methyl-2-(methylaminomethyl)-1H-indole (1.2 g, 6.9 mmole) for the1-methyl-3-(methylaminomethyl)-1H-indole, the title compound wasprepared. This was used without further purification.

b)(E)-3-(6-Amino-5-(methoxycarbonyl)pyridin-3-yl)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 15 (b), except substituting methyl2-amino-5-bromonicotinate (1.4 g, 6.1 mmole) for the5-bromo-2,2′-dipyridylamine, the title compound (1.78 g, 77%) wasprepared as a white solid: MS (ES) m/e379.2 (M+H)⁺.

Example 19 Preparation of(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide

To a stirred solution of(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]acrylic acidhydrochloride salt (2.0 g, 7.3 mmole) in 1:1 DMF/CH₂Cl₂ (100 mL) wasadded 2-methyl-3-(methylaminomethyl)indole (1.3 g, 7.5 mmole), Et₃N (2.1mL, 15 mmole), and HOBt H₂O (1.0 g, 7.4 mmole), followed by EDC (1.4 g,7.3 mmole). After stirring at room temperature for 18 h the reaction wasconcentrated to dryness. The residue was taken up in EtOAc, and thesolution was washed with H₂O then brine, dried (Na₂SO₄), andconcentrated under vacuum. The remaining residue was purified by flashchromatography on silica gel (4% MeOH/CHCl₃) to give the title compound(2.08 g, 73%) as an off-white solid: MS (ES) m/e 393.2 (M+H)⁺.

Example 20 Preparation of(E)-3-[6-[N-(carboxymethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide

To a stirred solution of(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide(0.5 g, 1.3 mmole) in dioxane (30 mL) was added 1 N NaOH (2 mL, 2mmole). After stirring for 18 h the reaction was neutralized with 1 NHCl (2 mL, 2 mmole) and concentrated to near dryness. The resultingsuspension was diluted with H₂O and filtered. The solid was washed withH₂O and dried under vacuum to give the title compound (505 mg, 100%) asa off-white solid: MS (ES) m/e 379.2 (M+H)⁺.

Example 21 Preparation of(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide

To(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide(0.7 g, 1.8 mmole) was added a solution of 2.0 M methylamine in MeOH (50mL). After stirring for 72 h the reaction was concentrated to dryness.The residue was triturated with Et₂O, filtered, and dried under vacuumto give the title compound (0.703 g, 100%) as an off-white solid: MS(ES) m/e 392.2 (M+H)⁺.

Example 22 Preparation of(E)-3-(2-aminopyrimidin-5-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)acrylamide

A solution of 2-amino-5-bromopyrimidine (0.27 g, 1.55 mmole),N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)acrylamide (0.5g, 2.33 mmole), Pd(OAc)₂ (0.037 g, 0.163 mmole), P(o-tolyl)₃ (0.085 g,0.28 mmole), and (i-Pr)₂NEt (0.42 mL, 2.33 mmole) in propionitrile (20mL) was degassed then heated to reflux. After 18 hr the mixture wascooled to RT and concentrated. Flash chromatography on silica gel (10%MeOH/CH₂Cl₂) gave the title compound (0.100 g, 18%): MS (ES) m/e 363(M+H)⁺.

Example 23 Preparation of(E)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 22, except substituting6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (0.352 g, 1.55 mmole) forthe 2-amino-5-bromopyrimidine, the title compound (0.14 g, 16%) wasprepared as a white powder: MS (ES) m/e 376 (M+H)⁺.

Example 24 Preparation of(E)-N-(2,3-dihydro-1H-3a-azacyclopenta[a]indene-8-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

EDC (0.192 g, 1.0 mmole) was added to a solution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt (0.254 g, 1.0 mmole),2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene (0.2 g,1.0 mmole), HOBt.H₂O (0.135 g, 1.0 mmole), and Et₃N (0.15 mL, 1.1 mmole)in DMF (20 mL) at RT. The reaction was stirred overnight, then waspoured into H₂O (50 mL) and extracted with CH₂Cl₂ (2×30 mL). Thecombined extracts were washed with brine and dried (MgSO₄). Flashchromatography on silica gel (5% MeOH/CH₂Cl₂) gave the title compound(0.1 g, 25%) a yellow solid: MS (ES) m/e 401 (M+H)⁺.

Example 25 Preparation of(E)-N-(1-ethyl-5-fluoro-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 24, except substituting(1-ethyl-5-fluoro-3-(methylaminomethyl)-1H-indole (0.1 g, 0.49 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,the title compound (0.028 g, 15%) was prepared as a white powder: MS(ES) m/e 407 (M+H)⁺.

Example 26 Preparation of(E)-N-(5-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 24, except substituting5-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.13 g, 0.67 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,the title compound (0.1 g, 37%) was prepared as a slightly yellowcrystalline solid: MS (ES) m/e 393 (M+H)⁺.

Example 27 Preparation of(E)-N-(5-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 24, except substituting6-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.12 g, 0.59 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,the title compound (0.1 g, 43%) was prepared as a white crystallinesolid: MS (ES) m/e 393 (M+H)⁺.

Example 28 Preparation of(E)-N-(7-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 24, except substituting7-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.18 g, 0.93 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,the title compound (0.1 g, 27%) was prepared as a white powder: MS (ES)m/e 393 (M+H)⁺.

Example 29 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(6-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 24, except substituting6-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.11 g, 0.59 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,and substituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.098 g, 0.59mmole) for the(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt, the title compound (0.1 g, 27%) was prepared as awhite powder: MS (ES) m/e 339 (M+H)⁺.

Example 30 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(4,6-dichloro-1-methyl-1H-indol-2-ylmethyl)-N-methylacrylamide

EDC (84.4 mg, 0.44 mmole) was added all at once to a solution of(E)-3-(6-aminopyridin-3-yl)acrylic acid (65.7 mg, 0.40 mmole),4,6-dichloro-1-methyl-2-(methylaminomethyl)-1H-indole (107.0 mg, 0.44mmole), HOBt.H₂O (59.5 mg, 0.44 mmole), and Et₃N (0.14 mL, 1.0 mmole) inanhydrous DMF (4 mL) at RT. After 17 hr, the reaction was concentratedto dryness and the residue was re-concentrated from CHCl₃/xylenes (2×).Flash chromatography on silica gel (7% MeOH in 1:1 EtOAc/CHCl₃) gave theR_(f) 0.44 component (10% MeOH in 1:1 EtOAc/CHCl₃) as a foam. This wassolidified by re-concentration from MeOH/EtOAc/CHCl₃ several times. Thismaterial was triturated with hot EtOAc/MeOH, and the mixture was cooledto 0° C. The title compound was collected by suction filtration. Thefiltrate was concentrated and the residue was triturated with EtOAc toafford additional title compound. The combined desired solids were driedin high vacuum at 50–60° C. to afford the title compound (108.9 mg, 70%)as a light yellow solid: ¹H NMR (400 MHz, CDCl₃) 1.8:1 mixture of amiderotamers; δ 8.08 –8.20 (2×s, 1 H), 7.70 –7.90 (2×d, 1 H), 7.57–7.70(2×s, 1 H), 7.46 (d, J=15.2 Hz, 1 H), 7.18 (s, 1 H), 6.97 (d, J=15.2 Hz,1 H), 6.45 and 6.15 (2×m, 4 H), 5.02 and 4.82 (2×s, 2 H), 3.60–3.80(2×s,3 H), 2.99 and 3.11 (2×s, 3 H); MS (ES) m/e 239 and 391 (M+H)⁺.

Example 31 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(1,4-dimethyl-1H-indole-3-ylmethyl)-N-methylacrylamide

To a stirred solution of 1,4-dimethyl-3-(methylaminomethyl)-1H-indole(188.2 mg, 1 mmole) and (E)-3-(6-aminopyridin-3-yl)acrylic acid (164 mg,1 mmole) in dry DMF (12 mL) containing dry Et₃N (4 mL) was addedHOBt.H₂O (153 mg, 1 mmole) and EDC (191.8 mg, 1 mmole). The reaction wasstirred overnight under argon at ambient temperature, then wasconcentrated in vacuo. The residue was partitioned between EtOAc and 5%NaHCO₃ solution, and the layers were separated. The organic layer waswashed with brine, dried (MgSO₄), filtered, and concentrated. Flashchromatography on silica gel afforded the title compound (120 mg, 36%)as a white solid: MS (ES) m/e 335.2 (M+H)⁺. Anal. Calcd forC₂₀H₂₂N₄O.0.25 H₂O: C, 70.88; H, 6.69; N, 16.53. Found: C, 71.11; H,6.72; N, 16.36.

Example 32 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(4-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 31, except substituting4-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-indole, the title compound (100 mg,29%) was obtained as a light yellow solid: MS (ES) m/e 351.2 (M+H)⁺.Anal. Calcd for C₂₀H₂₂N₄O₂.0.25 H₂O: C, 67.68; H, 6.39; N, 15.79. Found:C, 67.31; H, 6.21; N, 15.97.

Example 33 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(5-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 31, except substituting5-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound (110mg, 31%) was obtained as a light tan solid: MS (ES) m/e 351.2 (M+H)⁺.Anal. Calcd for C₂₀H₂₂N₄O₂.0.75 H₂O: C, 66.01; H, 6.51; N, 15.39. Found:C, 65.83; H, 6.29; N, 15.60.

Example 34 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(7-chloro-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 31, except substituting7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole for thedimethyl-3-(methylaminomethyl)-1H-indole, the title compound (180 mg,52%) as obtained as a yellow solid: MS (ES) m/e 355.2 (M+H)⁺. Anal.Calcd for C₁₉H₁₉ClN₄O.0.25 H₂O: C, 63.51; H, 5.47; N, 15.59. Found: C,63.55; H, 5.32; N, 15.68.

Example 35 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(7-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 31, except substituting7-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound (140mg, 40%) was obtained as a tan solid: MS (ES) m/e 351.2 (M+H)⁺. Anal.Calcd for C₂₀H₂₂N₄O₂.0.5 H₂O: C, 66.83; H, 6.45; N, 15.58. Found: C,66.81; H, 6.41; N, 15.19.

Example 36 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(6-chloro-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 31, except substituting6-chloro-1-methyl-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound (176mg, 50%) was obtained as a yellow solid: MS (ES) m/e 355.2 (M+H)⁺. Anal.Calcd for C₁₉H₁₉ClN₄O.0.5 H₂O: C, 62.72; H, 5.54; N, 15.40. Found: C,62.79; H, 5.20; N, 15.85.

Example 37 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(5-chloro-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 31, except substituting5-chloro-1-methyl-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole the title compound wasobtained as a tan solid (176 mg, 54%): MS (ES) m/e 355.2 (M+H)⁺. Anal.Calcd for C₁₉H₁₉ClN₄O.0.25 H₂O: C, 63.51; H, 5.47; N, 15.59. Found: C,63.63; H, 5.84; N, 15.83.

Example 38 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(4-chloro-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 31, except substituting4-Chloro-1-methyl-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-indole the title compound wasobtained as a tan solid (150 mg, 42%): MS (ES) m/e 355.2 (M+H)⁺. Anal.Calcd for C₁₉H₁₉ClN₄O.0.25 H₂O: C, 63.51; H, 5.47; N, 15.59. Found: C,63.33; H, 5.38; N, 15.34.

Example 39 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(3.3-dimethyl-3H-indene-1-ylmethyl)-N-methylacrylamide

According to the procedure of Example 31, except substituting1,1-dimethyl-3-(methylaminomethyl)-3H-indene for the1,4-dimethyl-3-(methylaminomethyl-1H-indole, the title compound (43 mg,13%) was obtained as a white solid: MS (ES) m/e 334.2 (M+H)⁺. Anal.Calcd for C₂₁H₂₃N₃O.0.75 H₂O: C, 72.70; H, 7.12; N, 12.11. Found: C,72.38; H, 6.80; N, 11.69.

Example 40 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(7-hydroxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 31, except substituting7-hydroxy-1-methyl-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound wasobtained as a tan solid (60 mg, 17.9%): MS (ES) m/e 337.2 (M+H)⁺. Anal.Calcd for C₁₉H₂₀N₄O₂.1.0 H₂O: C, 64.39; H, 6.26; N, 15.81. Found: C,63.99; H, 5.78; N, 15.54.

Example 41 Preparation of(E)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)-acrylamide

a) N-Methyl-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)acrylamide

To a cold solution (ice bath) of3-(methylaminomethyl)-1,2,7-trimethyl-1H-indole (570 mg, 2.8 mmole) indry CH₂Cl₂ (24 mL) was added dry Et₃N (0.25 mL, 2.9 mmole). The reactionwas stirred in the cold under argon for 2 h then was poured into H₂O (40mL). The layers were separated, and the organic layer was washed withbrine, dried (MgSO₄), filtered, and concentrated. The title compound(0.7 g, 97%) was obtained as a light orange solid: MS (ES) m/e 257.2(M+H)⁺.

b)(E)-N-Methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)-acrylamide

A mixture of N-methyl-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)acrylamide(256 mg, 1 mmole) and 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (227mg, 1 mmole) in propionitrile (20 mL) was treated with DIEA (0.3 mL),Pd(OAc)₂ (29 mg, 0.13 mmole), and tri-o-tolylphosphine (50 mg, 0.16mmole). The reaction was heated at reflux under argon for 10 h, then wascooled to RT and filtered through supercel. The filtrate wasconcentrated and the residue was purified by flash chromatography onsilica gel to afford the title compound (100 mg, 25%) as an off-whitesolid: MS (ES) m/e 403.2 (M+H)⁺. Anal. Calcd for C₂₄H₂₆N₄O₂.2.75 H₂O: C,63.77; H, 7.02; N, 12.39. Found: C, 63.81; H, 7.25; N, 11.90.

Example 42 Preparation of(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylamide

A solution of 7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole (104.3mg, 0.5 mmole) and(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid(109.1 mg, 0.5 mmole) in dry DMF (8 mL) was treated with dry Et₃N (0.2mL), HOBt.H₂O (76.5 mg, 0.5 mmole) and EDC (96 mg, 0.5 mmole). Thesolution was stirred at RT under argon for 20 h, then was concentrated.The oily residue was dissolved in MeOH and the solution was cooled. Theprecipitated solid was collected, washed with cold MeOH, and dried togive the title compound (95 mg, 47%): MS (ES) m/e 409.2 (M+H)⁺. Anal.Calcd for C₂₂H₂₁ClN₄O₂.0.25 H₂O: C, 63.92; H, 5.24; N, 13.55. Found: C,63.56; H, 5.14; N, 13.73.

Example 43 Preparation of(E)-N-(7-chloro-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylamide

According to the procedure of Example 42, except substituting7-chloro-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(25 mg, 13%) was obtained as an off white solid after chromatography onsilica gel: MS (ES) m/e 395.0 (M+H )⁺

Example 44 Preparation of(E)-2,N-dimethyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 4, except substituting(E)-2-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylicacid hydrochloride salt (0.50 g, 1.8 mmole) for the(E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt,the title compound (0.64 g, 89%) was prepared as a light yellow solid:MS (ES) m/e 389 (M+H)⁺.

Example 45 Preparation of(E)-3,N-dimethyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 4, except substituting(E)-3-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylicacid hydrochloride salt (0.50 g, 1.8 mmole) for the(E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt,the title compound (0.67 g, 92%) was prepared as a light yellow solid:MS (ES) m/e 389 (M+H)⁺.

Example 46 Preparation of(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e]-1.4-diazepin-7-yl)acrylamide

According to the procedure of Example 1, except substituting7-bromo-4-methyl-1,2,4,5-tetrahydropyrido[2,3-e]-1,4-diazepin-3-one(0.50 g, 1.9 mmole) for the 2-amino-5-bromopyrimidine, the titlecompound (0.30 g, 62%) was prepared as a light yellow solid: MS (ES) m/e404 (M+H)⁺.

Example 47 Preparation of (E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide

EDC (0.18 g, 0.96 mmole) was added to a solution of(E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylic acidhydrochloride salt (0.24 g, 0.87 mmole),2-methyl-3-(methylaminomethyl)indole (0.15 g, 0.87 mmole), HOBt.H₂O(0.13 g., 0.96 mmole) and diisopropylethylamine (0.45 mL, 2.61 mmole) inDMF (15 mL) at RT. The reaction was stirred overnight then wasconcentrated in vacuo. The residue was diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed with brineand dried over Na₂SO₄. Preparative HPLC on a Waters C-18 ODSA column(gradient: 20–100% H₂O/CH₃CN) gave the title compound (0.13 g, 38%) as alight yellow solid after drying in vacuo: MS (ES) m/e 389 (M+H)⁺.

Example 48 Preparation of(E)-N-[1-(2-hydroxyethyl)-1H-indol-3-ylmethyl]-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

EDC (0.54 g, 2.80 mmole) was added to a solution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt (0.71 g, 2.80 mmole),1-(2-hydroxyethyl)-3-(methylaminomethyl)-1H-indole (0.52 g, 2.55 mmole),HOBt.H₂O (0.38 g., 2.80 mmole) and diisopropylethylamine (1.11 mL, 6.40mmole) in DMF (25 mL) at RT. The reaction was stirred overnight then wasconcentrated in vacuo. The residue was diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed with brineand dried over Na₂SO₄. Flash chromatography on silica gel (20%EtOH/EtOAc) gave title compound (0.28 g, 27%) as an off-white solidafter drying in vacuo: MS (ES) m/e 405 (M+H)⁺.

Example 49 Preparation of(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide)

EDC (0.06 g, 0.30 mmole) was added to a solution of(E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylic acidhydrochloride salt (0.07 g, 0.27 mmole),1-methyl-3-(methylaminomethyl)-1H-indole (0.05 g, 0.27 mmole), HOBt.H₂O(0.04 g., 0.30 mmole) and diisopropylethylamine (0.14 mL, 0.81 mmole) inDMF (15 mL) at RT. The reaction was stirred overnight then wasconcentrated in vacuo. The residue was diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed with brineand dried over Na₂SO₄. Flash chromatography on silica gel (20%EtOH/EtOAc) gave title compound (0.05 g, 48%) as an off-white solidafter drying in vacuo: MS (ES) m/e 389 (M+H)⁺.

Example 50 Preparation of(E)-N-[1-(2-hydroxyethyl)-1H-indol-3-ylmethyl]-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

EDC (0.35 g, 1.81 mmole) was added to a solution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt (0.42 g, 1.65 mmole),1-ethyl-3-(methylaminomethyl)-1H-indole (0.31 g, 1.65 mmole), HOBt.H₂O(0.24 g., 1.81 mmole) and diisopropylethylamine (0.86 mL, 4.95 mmole) inDMF (15 mL) at RT. The reaction was stirred overnight then wasconcentrated in vacuo. The residue was diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed with brineand dried over Na₂SO₄. Flash chromatography on silica gel (10%EtOH/EtOAc) gave title compound (0.39 g, 61%) as a light yellow solidafter drying in vacuo: MS (ES) m/e 389 (M+H)⁺.

Example 51 Preparation of(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methylacrylamide

According to the procedure of Example 19, except substituting7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole (1.4 g, 6.7 mmole) forthe 2-methyl-3-(methylaminomethyl)indole, the title compound (2.38 g,84%) was prepared as a pale yellow solid: MS (ES) m/e 427.0 (M+H)⁺.

Example 52 Preparation of(E)-3-[6-[N-(carboxymethyl)amino]pyridin-3-yl]-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 20, except substituting(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methylacrylamide(0.75 g, 1.8 mmole) for the(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide,the title compound (0.746 g, 100%) was prepared as a white solid: MS(ES) m/e 413.2 (M+H)⁺.

Example 53 Preparation of(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide

According to the procedure of Example 21, except substituting(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methylacrylamide(0.75 g, 1.8 mmole) for the(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide,the title compound (0.721 g, 94%) was prepared as a white solid: MS (ES)m/e 426.0 (M+H)⁺.

Example 54 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(2-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 31, except substituting2-chloro-1-methyl-2-(methylaminomethyl)-1H-indole (0.7 g, 3.0 mmole) forthe 1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound(0.935 g, 88%) was obtained as an off-white solid: MS (ES) m/e 355.2(M+H)⁺.

Example 55 Preparation of(E)-N-(2-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 24, except substituting2-chloro-1-methyl-2-(methylaminomethyl)-1H-indole (0.7 g, 3.0 mmole) forthe 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, thetitle compound (1.03 g, 84%) was obtained as a white solid: MS (ES) m/e409.0 (M+H)⁺.

Example 56 Preparation of(E)-N-(naphthalen-2-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 24, except substituting2-(methylaminomethyl)naphthalene (0.55 g, 3.2 mmole) for the2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, thetitle compound (0.871 g, 73%) was obtained as a white solid: MS (ES) m/e372.2 (M+H)⁺.

Example 57 Preparation of(E)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(6-amino-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

a)(E)-N-(1-Methyl-1H-indol-3-ylmethyl)-N-methyl-3-[6-(benzhydrylideneamino)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]acrylamide

According to the procedure of Example 15, except substituting3-(benzhydrylideneamino)-6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one(3.5 g, 8.6 mmole) for the 5-bromo-2,2′-dipyridylamine, the titlecompound (3.72 g, 78%) was obtained as a pale yellow solid: MS (ES) m/e554.4 (M+H)⁺.

b)(E)-N-(1-Methyl-1H-indol-3-ylmethyl)-N-methyl-3-(6-amino-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

To a suspension of(E)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-[6-(benzhydrylideneamino)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]acrylamide(0.5 g, 0.9 mmole) in dioxane (15 mL) was added 1 N HCl (10 mL) withstirring at RT. After approximately 5 min the suspension cleared up thengradually reformed. After stirring for 1 h the reaction was neutralizedwith 1 N NaOH (10 mL) and concentrated to near dryness under vacuum. Theresulting suspension was diluted with H₂O (20 mL) and filtered, and thesolid was rinsed with cold H₂O and dried under vacuum. The slightlypinkish solid was triturated with Et₂O, filtered, and dried under vacuumto give the title compound (248 mg, 71%) as an off-white solid: MS (ES)m/e 390.4 (M+H)⁺.

Example 58 Preparation of(E)-N-(benzofuran-2-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 4, except substituting(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt (1.60 g, 6.3 mmole) for the(E)-3-(2-oxo[2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt,and substituting 2-(methylaminomethyl)benzofuran (1.20 g, 6.9 mmole) forthe 2-methyl-3-(methylaminomethyl)indole, the title compound (2.0 g,90%) was prepared as a tan solid: MS (ES) m/e 363 (M+H)⁺.

Example 59 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(7-methoxycarbonyl-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 31, except substituting methyl1-methyl-3-(methylaminomethyl)-1H-indole-7-carboxylate for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound (150mg, 34%) was obtained, after trituration with diethyl ether, as anoff-white solid: MS (ES) m/e379.2 (M+H)⁺. Anal. Calcd forC₂₁H₂₂N₄O₃.0.25 H₂O: C, 65.87; H, 5.92; N, 14.63. Found: C, 66.02; H,5.71; N, 14.29.

Example 60 Preparation of(E)-3-(aminopyridin-3-yl)-N-methyl-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)acrylamide

According to the procedure of Example 31, except substituting3-(methylaminomethyl)-1,2,7-trimethyl-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound (120mg, 29%) was obtained, after trituration with ethyl acetate, as a lightyellow solid: MS (ES) m/e 349.0 (M+H)⁺. Anal. Calcd for C₂₁H₂₄N₄O.H₂O:C, 68.82; H, 7.69; N, 15.29. Found: C, 68.42; H, 6.86; N, 15.61.

Example 61 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(7-chloro-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 31, except substituting7-chloro-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound (150mg, 25%) was obtained, after trituration with ethyl acetate, as a lightyellow solid: MS (ES) m/e 341.0 (M+H)⁺. Anal. Calcd for C₁₈H₁₇N₄O.0.25H₂O: C, 62.60; H, 5.10; N, 16.22. Found: C, 62.29; H, 5.01; N, 16.32.

Example 62 Preparation of(E)-N-(5-chloro-1-methyl-1H-indol-3ylmethyl-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 42, except substituting5-chloro-1-methyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(100 mg, 49%) was obtained as a light tan solid: MS (ES) m/e 409.0(M+H)⁺. Anal. Calcd for C₂₂H₂₁ClN₄O₂.0.5 H₂O: C, 63.23; H, 5.32; N,13.40. Found: C, 63.19; H, 5.23; N, 13.45.

Example 63 Preparation of (E)-N-(6-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 42, except substituting6-chloro-1-methyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(125 mg, 61%) was obtained as a light tan solid: MS (ES) m/e 409.0(M+H)⁺. Anal. Calcd for C₂₂H₂₁ClN₄O₂.0.25 H₂O: C, 63.92; H, 5.24; N,13.55. Found: C, 63.96; H, 4.98; N, 13.66.

Example 64 Preparation of (E)-N-(1,7-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 42, except substituting1,7-dimethyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(100 mg, 51%) was obtained as a white solid: MS (ES) m/e 389.2 (M+H)⁺.Anal. Calcd for C₂₃H₂₄N₄O₂.0.25 H₂O: C, 70.29; H, 6.28; N, 14.25. Found:C, 70.06; H, 6.23; N, 14.29

Example 65 Preparation of(E)-N-(1,6-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 42, except substituting1,6-dimethyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(95 mg, 49%) was obtained as a white solid: MS (ES) m/e389.2 (M+H)⁺.Anal. Calcd for C₂₃H₂₄N₄O₂.0.75 H₂O: C, 68.72; H, 6.39; N, 13.93. Found:C, 68.98; H, 6.07; N, 13.81.

Example 66 Preparation of(E)-N-(1,4-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 42, except substituting1,4-dimethyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(90 mg, 46%) was obtained as a white solid: MS (ES) m/e 389.0 (M+H)⁺.Anal. Calcd for C₂₃H₂₄N₄O₂.0.5 H₂O: C, 69.50; H, 6.33; N, 14.10. Found:C, 69.40; H, 6.24; N, 14.20.

Example 67 Preparation of(E)-N-(1,5-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 42, except substituting1,5-dimethyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(100 mg, 51%) was obtained as a white solid: MS (ES) m/e 389.2 (M+H)⁺.Anal. Calcd for C₂₃H₂₄N₄O₂.0.125 H₂O: C, 70.70; H, 6.25; N, 14.34.Found: C, 70.75; H, 6.15; N, 14.38.

Example 68 Preparation of(E)-N-(7-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 42, except substituting7-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(85 mg, 42%) was obtained as an off-white solid: MS (ES) m/e 405.2(M+H)⁺. Anal. Calcd for C₂₃H₂₄N₄O₃: C, 68.30; H, 5.95; N, 13.85. Found:C, 67.95; H, 5.94; N, 13.94.

Example 69 Preparation of(E)-N-(7-hydroxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 42, except substituting7-hydroxy-1-methyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(200 mg, 51%) was obtained as a tan solid: MS (ES) m/e 391.2 (M+H)⁺.Anal. Calcd for C₂₂H₂₂N₄O₃.0.75 H₂O: C, 65.41; H, 5.85; N, 13.86. Found:C, 65.25; H, 5.95; N, 13.79.

Example 70 Preparation of (E)-N-(4-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 42, except substituting4-chloro-1-methyl-3-(methylaminomethyl for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(100 mg, 49%) was obtained as a white solid: MS (ES) m/e 409.0 (M+H)⁺.Anal. Calcd for C₂₂H₂₁ClN₄O₂.0.75 H₂O: C, 62.55; H, 5.36; N, 13.26.Found: C, 62.71; H, 5.24; N, 13.15.

Example 71 Preparation of(E)-N-(4-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1.8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 42, except substituting4-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(65 mg, 32%) was obtained as an off-white solid: MS (ES) m/e 405.2(M+H)⁺. Anal. Calcd for C₂₃H₂₄N₄O₃.1.25 H₂O: C, 64.69; H, 6.19; N,13.33. Found: C, 64.49; H, 5.94; N, 13.76

Example 72 Preparation of(E)-N-(5-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 42, except substituting5-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(90 mg, 44%) was obtained as an off-white solid: MS (ES) m/e 405.2(M+H)⁺. Anal. Calcd for C₂₃H₂₄N₄O₃ 0.5 H₂O: C, 66.81; H, 6.09; N, 13.55.Found: C, 66.67; H, 5.96; N, 13.87.

Example 73 Preparation of (E)3-(6-aminopyridin-3-yl)-N-(7-carboxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

A solution of(E)-3-(6-aminopyridin-3-yl)-N-(7-methoxycarbonyl-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide(76 mg, 0.2 mmole) in methanol (4 mL), water (2 mL), and tetrahydrofuran(2 mL) was treated with LiOH (39 mg, 1.6 mmole), and the reaction wasstirred at ambient temperature for 48 h. The mixture was filtered, andthe filtrate was acidified to pH 4.0–4.5 with 1.0 N HCl. The precipitatewas collected, washed with water and dried giving the title compound (25mg, 35%) as a white solid: MS (ES) m/e 365.2 (M+H)⁺. Anal. Calcd forC₂₀H₂₀N₄O₃.0.25 H₂O: C, 65.11: H, 5.60; N, 15.18. Found: C, 64.83; H,5.52; N, 15.07.

Example 74 Preparation of(E)-N-(6-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 42, except substituting6-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole for the7-chloro-I-methyl-3-(methylaminomethyl)-1H-indole, the title compound(65 mg, 32%) was obtained as a yellow solid: MS (ES) m/e405.2 (M+H)⁺.Anal. Calcd for C₂₃H₂₄N₄O₃.H₂O: C, 65.38; H, 6.20; N, 13.26. Found: C,65.36; H, 5.98; N, 13.16.

Example 75 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(6-methoxycarbonyl-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 31, except substituting methyl1-methyl-3-(methylaminomethyl)-1H-indole-6-carboxylate for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound (168mg, 39%) was obtained, after silica gel chromatography, as a whitesolid: MS (ES) m/e 379.2 (M+H)⁺. Anal. Calcd for C₂₁H₂₂N₄O₃.0.125 H₂O:C, 66.25; H, 5.93; N, 14.71. Found: C, 66.60; H, 6.13; N, 14.18.

Example 76 Preparation of(E)-N-(3,3-dimethyl-3H-indene-1-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 42, except substituting3,3-dimethyl-1-(methylaminomethyl)-3H-indene for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(48 mg, 12%) was obtained, after silica gel chromatography, as a tansolid: MS (ES) m/e 388.2 (M+H)⁺. Anal. Calcd for C₂₃H₂₄N₄O₃.0.375 H₂O:C, 73.31; H, 6.51; N, 10.66. Found: C, 72.91; H, 6.37; N, 11.16.

Example 77 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(4-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 24, except substituting4-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.2 g, 1.04 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,and substituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.17 g, 1.04mmole) for the(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt, the title compound (0.11 g, 37%) was prepared as anoff-white powder: MS (ES) m/e 339 (M+H)⁺.

Example 78 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(5-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 24, except substituting5-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.2 g, 1.04 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,and substituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.17 g, 1.04mmole) for the(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt, the title compound (0.14 g, 41%) was prepared as anoff-white powder: MS (ES) m/e 339 (M+H)⁺.

Example 79 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(7-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 24, except substituting7-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.2 g, 1.04 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,and substituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.17 g, 1.04mmole) for the(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt, the title compound (0.1 g, 27%) was prepared as anoff-white powder: MS (ES) m/e 339 (M+H)⁺.

Example 80 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(4-fluoro-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 24, except substituting4-fluoro-3-(methylaminomethyl)-1H-indole (0.31 g, 1.74 mmole) for the2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, andsubstituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.285 g, 1.74mmole) for the(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt, the title compound (0.2 g, 36%) was prepared as awhite powder: MS (ES) m/e 325 (M+H)⁺.

Example 81 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(7-fluoro-1H-indol-3-ylmethyl)-N-methylacrylamide

According to the procedure of Example 24, except substituting7-fluoro-3-(methylaminomethyl)-1H-indole (0.31 g, 1.74 mmole) for the2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, andsubstituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.285 g, 1.74mmole) for the(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt, the title compound (0.1 g, 18%) was prepared as awhite powder: MS (ES) m/e 325 (M+H)⁺.

Example 82 Preparation of(E)-N-(4-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 24, except substituting4-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.13 g, 0.68 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene),the title compound (0.15 g, 56%) was prepared as an off-white powder: MS(ES) m/e 393 (M+H)⁺.

Example 83 Preparation of(E)-N-(quinolin-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 24, except substituting3-(methylaminomethyl)quinoline (0.12 g, 0.67 mmole) for the2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene), thetitle compound (0.1 g, 40%) was prepared as an off-white powder: MS (ES)m/e 373 (M+H)⁺.

Example 84 Preparation of(E)-N-(naphthalen-1-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 24, except substitutingN-methyl-1-naphthalenemethylamine hydrochloride (0.162 g, 0.95 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene),the title compound (0.15 g, 43%) was prepared as a white powder: MS (ES)m/e 372 (M+H)⁺.

Example 85 Preparation of(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-[3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl]acrylamide

A solution of6-bromo-3-(2-methoxyethyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one(0.86 g, 3.00 mmole),N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide (see Example 1 (a),0.68 g, 3.00 mmole), Pd(OAc)₂ (0.07 g, 0.30 mmole),tri-ortho-tolylphosphine (0.18 g, 0.60 mmole) and diisopropylethylamine(1.31 mL, 7.50 mmole) in propionitrile (50 mL) was deoxygenated, thenwas heated at reflux under N₂ overnight. The dark mixture was filteredthrough a pad of celite®, and the filter pad was rinsed withacetonitrile (250 mL). The filtrate was concentrated in vacuo, and theresidue was purified by flash chromatography on silica gel (10%EtOAc/EtOH). The title compound (0.46 g, 36%) was obtained as a lightyellow solid after drying in vacuo: MS (ES) m/e 434 (M+H)⁺.

Example 86 Preparation of(E)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(6-methoxycarbonyl-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

According to the procedure of Example 15 (b), except substituting methyl(+)-6-bromo-2-oxo-1,2,3,4-tetrahydro-1H-1,8-naphthyridine-3-carboxylate(2.5 g, 8.8 mmole), from Preparation 4 (d), for the5-bromo-2,2′-dipyridylamine, the title compound (1.82 g, 48%) wasprepared as an off-white solid: MS (ES) m/e 433.4 (M+H)⁺.

Example 87 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(1.3-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-N-methylacrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 88 Preparation of(E)-N-(1.3-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 89 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 90 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 91 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 92 Preparation of(E)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 93 Preparation of(E)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 94 Preparation of(E)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 95 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(benzofuran-3-ylmethyl)-N-methylacrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 96 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 97 Preparation of(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(2-methylbenzofuran-3-ylmethyl)acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 98 Preparation of(E)-N-(benzofuran-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 99 Preparation of(E)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 100 Preparation of(E)-N-methyl-N-(2-methylbenzofuran-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 101 Preparation of(E)-(6-aminopyridin-3-yl)-N-methyl-N-[1-(1-methyl-1H-indol-2-yl)ethyl]acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 102 Preparation of(E)-(6-aminopyridin-3-yl)-N-methyl-N-[1-(1-methyl-1H-indol-3-yl)ethyl]acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 103 Preparation of(E)-N-methyl-N-[1-(1-methyl-1H-indol-2-yl)ethyl]-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 104 Preparation of(E)-N-methyl-N-[1-(1-methyl-1H-indol-3-yl)ethyl]-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

The title compound is prepared following methods analogous to thosedescribed in the previous preparations and examples.

Example 105 Parenteral Dosage Unit Composition

A preparation which contains 20 mg of the compound of Example 1 as asterile dry powder is prepared as follows: 20 mg of the compound isdissolved in 15 mL of distilled water. The solution is filtered understerile conditions into a 25 mL multi-dose ampoule and lyophilized. Thepowder is reconstituted by addition of 20 mL of 5% dextrose in water(D5W) for intravenous or intramuscular injection. The dosage is therebydetermined by the injection volume. Subsequent dilution may be made byaddition of a metered volume of this dosage unit to another volume ofD5W for injection, or a metered dose may be added to another mechanismfor dispensing the drug, as in a bottle or bag for IV drip infusion orother injection-infusion system.

Example 106 Oral Dosage Unit Composition

A capsule for oral administration is prepared by mixing and milling 50mg of the compound of Example 1 with 75 mg of lactose and 5 mg ofmagnesium stearate. The resulting powder is screened and filled into ahard gelatin capsule.

Example 107 Oral Dosage Unit Composition

A tablet for oral administration is prepared by mixing and granulating20 mg of sucrose, 150 mg of calcium sulfate dihydrate and 50 mg of thecompound of Example 1 with a 10% gelatin solution. The wet granules arescreened, dried, mixed with 10 mg starch, 5 mg talc and 3 mg stearicacid; and compressed into a tablet.

The above description fully discloses how to make and use the presentinvention. However, the present invention is not limited to theparticular embodiments described hereinabove, but includes allmodifications thereof within the scope of the following claims. Thevarious references to journals, patents and other publications which arecited herein comprises the state of the art and are incorporated hereinby reference as though fully set forth.

1. A compound according to formula (I):

wherein:

R¹ is H, C₁₋₄alkyl, —C₀₋₆alkyl-Ar, —(CH₂)₁₋₃N(R′)₂, or —(CH₂)₁₋₃OR; R²is H, C₁₋₄alkyl or C₃₋₆cycloalkyl; R³ is

or R⁴ is H or C₁₋₄alkyl;

indicates that one of the two designated bonds is a double bond and theother is a single bond; R⁵ is CH₂ when the bond to which it is attachedis a double bond; or R⁵ is H or C₁₋₄alkyl when the bond to which it isattached is a single bond; R⁶ is H or C₁₋₄alkyl; each R⁷ independentlyis H, C₁₋₆alkyl, —C₀₋₆alkyl-Ar, —(CH₂)₁₋₃N(R′)₂, or —(CH₂)₁₋₃OR′; R⁸ isH or C₁₋₄alkyl; R⁹ and R⁹′ independently are H or C₁₋₄alkyl; R¹⁰ isC₁₋₄alkyl, N(R′)₂, NHC(O)R′, NHCH₂C(O)R′ or NHC(O)CH═CHR′; Y* is N(R′)₂,NHC(O)R′, NHCH₂C(O)R′ or NHC(O)CH═CHR′; each X independently is H,C₁₋₄alkyl, CH₂OH, OR′, SR′CN, N(R′)₂, CH₂N(R′)₂, NO₂, CF₃, CO₂R′,CON(R′)₂, COR′, NR′C(O)R′, F, Cl, Br, I or —S(O)_(r)CF₃; X* is—(CH₂)₁₋₃C(O)N(R′)—(CH₂)₁₋₃—Ar or —(CH₂)₁₋₃C(O)N(R′)—(CH₂)₁₋₃-Het; W isS or O; Q is H or C₁₋₄alkyl; each R′ independently is H, C₁₋₆alkyl,—CO₀₋₆alkyl-Ar or —C₀₋₆alkyl-Het; and r is 0, 1 or 2; or apharmaceutically acceptable salt thereof.
 2. A compound which is:(E)-3-[6-amino-5-[[N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)amino]carbonylethyl]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide;(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide;(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(8oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3yl)acrylamide;(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide;or a pharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition which comprises a compound according to claims 1 or 2 and apharmaceutically acceptable carrier.
 4. A method of treating bacterialinfections which comprises administering to a subject in need thereof atherapeuticall effective amount of a compound according to claim 1 or 2.